Rabih M. Salloum

Association between Intraoperative Blood Transfusion and Mortality and Morbidity in Patients Undergoing Noncardiac Surgery

Background:The impact of intraoperative erythrocyte transfusion on outcomes of anemic patients undergoing noncardiac surgery has not been well characterized. The objective of this study was to examine the association between blood transfusion and mortality and morbidity in patients with severe anemia (hematocrit less than 30%) who are exposed to one or two units of erythrocytes intraoperatively. Methods:This was a retrospective analysis of the association of blood transfusion and 30-day mortality and 30-day morbidity in 10,100 patients undergoing general, vascular, or orthopedic surgery. We estimated separate multivariate logistic regression models for 30-day mortality and for 30-day complications. Results:Intraoperative blood transfusion was associated with an increased risk of death (odds ratio [OR], 1.29; 95% CI, 1.03–1.62). Patients receiving an intraoperative transfusion were more likely to have pulmonary, septic, wound, or thromboembolic complications, compared with patients not receiving an intraoperative transfusion. Compared with patients who were not transfused, patients receiving one or two units of erythrocytes were more likely to have pulmonary complications (OR, 1.76; 95% CI, 1.48–2.09), sepsis (OR, 1.43; 95% CI, 1.21–1.68), thromboembolic complications (OR, 1.77; 95% CI, 1.32–2.38), and wound complications (OR, 1.87; 95% CI, 1.47–2.37). Conclusions:Intraoperative blood transfusion is associated with a higher risk of mortality and morbidity in surgical patients with severe anemia. It is unknown whether this association is due to the adverse effects of blood transfusion or is, instead, the result of increased blood loss in the patients receiving blood.

Prophylactic glutamine protects the intestinal mucosa from radiation injury.

Glutamine may be an essential dietary component, especially for the support of intestinal mucosal growth and function. This study evaluated the effects of a glutamine‐enriched elemental diet, administered before whole‐abdominal radiation on gut glutamine metabolism, mucosal morphometrics, and bacterial translocation. Rats were randomized to receive a nutritionally complete elemental diet that was glutamine‐enriched or glutamine‐free for 4 days. The animals were then subjected to a single dose of 1000 cGy x‐radiation to the abdomen. After irradiation, all animals received the glutamine‐free diet. Four days later the animals underwent laparotomy for sampling of arterial and portal venous blood, culture of mesenteric lymph nodes, and removal of the small intestine for microscopic examination. There was no difference in arterial glutamine or gut glutamine extraction between the two groups, but body weight loss was significantly diminished in the glutamine‐fed rats. Rats receiving the glutamine‐enriched elemental diet before radiation had a significant increase in jejunal villous number, villous height, and number of metaphase mitoses per crypt. Scanning electron microscopy confirmed the presence of an intact gut epithelium in eight of eight rats receiving prophylactic glutamine compared to one of eight animals in the glutamine‐free group. Three of eight rats fed glutamine had culture positive mesenteric lymph nodes compared with five of seven rats receiving the glutamine‐free diet. Glutamine exerts a protective effect on the small bowel mucosa by supporting crypt cell proliferation which may accelerate healing of the acutely radiated bowel.

The effects of sepsis and endotoxemia on gut glutamine metabolism.

The effects of sepsis on gut glutamine (GLN) metabolism were studied to gain further insight into the regulation of the altered glutamine metabolism that characterizes critical illnesses. Studies were done in laboratory rats and in hospitalized patients. The human studies were done in seven healthy surgical patients (controls) and six septic patients who underwent laparotomy. Radial artery and portal vein samples were obtained during operation and were analyzed for GLN and oxygen content. Despite no reduction in arterial glutamine concentration in the septic patients, gut glutamine extraction was diminished by 75% (12.0% +/- 1.6% in controls vs. 2.8% +/- 0.8% in septic patients, p less than 0.01). Similarly gut oxygen extraction was diminished by nearly 50% in the septic patients (p less than 0.05). To further investigate these abnormalities, endotoxin (10 mg/kg intraperitoneally) or saline (controls) was administered to adult rats 12 hours before cannulation of the carotid artery and portal vein. The arterial GLN concentration was increased by 13% in the endotoxin-treated animals (p less than 0.05) but gut glutamine uptake was diminished by 46% (526 +/- 82 nmol/100 g BW/minute in controls vs. 282 +/- 45 in endotoxin, p less than 0.01). Simultaneously gut glutaminase activity was diminished by 30% (p less than 0.01) and intestinal glutamate release fell by two thirds. Blood cultures were negative in control animals (0 of 20), but were positive in 25% of endotoxemic animals (6 of 24) for gram-negative rods (p = 0.019). Sepsis and endotoxemia impair gut glutamine metabolism. This impairment may be etiologic in the breakdown of the gut mucosal barrier and in the development of bacterial translocation.

Glutamine-enriched diets support muscle glutamine metabolism without stimulating tumor growth

Glutamine is a principal fuel utilized by rapidly growing tumors. Advanced malignant disease results in muscle glutamine depletion and weight loss. Concern exists about providing dietary glutamine to the host with cancer since it may stimulate tumor growth. This study examined the effects of oral glutamine on muscle glutamine metabolism and tumor growth. Twenty-four rats with large sarcomas were pair fed a glutamine-enriched or glutamine-free elemental diet. Diets were isonitrogenous and isocaloric. After 6 days of feeding, the animals were anesthetized and arterial glutamine, hindquarter glutamine flux, muscle glutamine content, tumor weight, tumor DNA content, tumor glutaminase activity, and number of metaphase mitoses/high power field (HPF) in the tumor were determined. There was no difference in arterial glutamine between the two groups, but provision of a glutamine-enriched diet increased muscle glutamine content by 60% (2.31 +/- 0.21 mumole/g tissue vs 1.44 +/- 0.22 mumol/g tissue, P less than 0.05), which supported muscle glutamine release. There were no differences among tumor DNA content, tumor glutaminase activity, or tumor weight and there was no difference histologically in the number of metaphase mitoses/HPF. Glutamine-enriched oral diets may replete host glutamine stores and support muscle glutamine metabolism without stimulating tumor growth.

Perioperative outcomes among patients with the modified metabolic syndrome who are undergoing noncardiac surgery.

Background:Previous studies have demonstrated that obesity is paradoxically associated with a lower risk of mortality after noncardiac surgery. This study will determine the impact of the modified metabolic syndrome (defined as the presence of obesity, hypertension, and diabetes) on perioperative outcomes. Methods:This study is based on data from 310,208 patients in the American College of Surgeons National Surgical Quality Improvement Program database. We estimated separate multivariate logistic regression models for 30-day mortality and for 30-day complications. Results:Patients with the modified metabolic syndrome who are super obese had a 2-fold increased risk of death (adjusted odds ratio [AOR] 1.99; 95% CI 1.41–2.80). As stratified by body mass index, patients with the modified metabolic syndrome had a 2- to 2.5-fold higher risk of cardiac adverse events (CAE) compared with normal-weight patients: obese (AOR 1.70; 95% CI 1.40–2.07), morbidly obese (AOR 2.01; 95% CI 1.48–2.73), and super obese (AOR 2.66; 95% CI 1.68–4.19). In addition, the risk of acute kidney injury (AKI) was 3- to 7-fold higher in these patients: obese (AOR 3.30; 95% CI 2.75–3.94), morbidly obese (AOR 5.01; 95% CI 3.87–6.49), and super obese (AOR 7.29; 95% CI 5.27–10.1). Conclusion:Patients with the modified metabolic syndrome undergoing noncardiac surgery are at substantially higher risk of complications compared with patients of normal weight.

Brush border transport of glutamine and other substrates during sepsis and endotoxemia.

The effects of severe infection on luminal transport of amino acids and glucose by the small intestine were investigated. Studies were done in endotoxin-treated rats and in septic patients who underwent resection of otherwise normal small bowel. In rats the kinetics of the brush border glutamine transporter and the glutaminase enzyme were examined. In patients the effects of severe infection on the transport of glutamine, alanine, leucine, and glucose were studied. Transport was measured using small intestinal brush border membrane vesicles that were prepared by Mg++ aggregation/differential centrifugation. Uptake of radiolabeled substrate was measured using a rapid mixing/filtration technique. Vesicles demonstrated 15-fold enrichments of enzyme markers, classic overshoots, transport into an osmotically active space, and similar 2-hour equilibrium values. The sodium-dependent pathway accounted for nearly 90% of total carrier-mediated transport. Kinetic studies on rat jejunal glutaminase indicated a decrease in activity as early as 2 hours after endotoxin secondary to a decrease in enzyme affinity for glutamine (Km = 2.23 +/- 0.20 mmol/L [millimolar] in controls versus 4.55 +/- 0.67 in endotoxin, p less than 0.03), rather than a change in Vmax. By 12 hours the decrease in glutaminase activity was due to a decrease in Vmax (222 +/- 36 nmol/mg protein/min in controls versus 96 +/- 16 in endotoxin, p less than 0.03) rather than a significant change in Km. Transport data indicated a decrease in sodium-dependent jejunal glutamine uptake 12 hours after endotoxin secondary to a 35% reduction in maximal transport velocity (Vmax = 325 +/- 12 pmol/mg protein/10 sec in controls versus 214 +/- 8 in endotoxin, p less than 0.0001) with no change in Km (carrier affinity). Sodium-dependent glutamine transport was also decreased in septic patients, both in the jejunum (Vmax for control jejunum = 786 +/- 96 pmol/mg protein/10 sec versus 417 +/- 43 for septic jejunum, p less than 0.01) and in the ileum (Vmax of control ileum = 1126 +/- 66 pmol/mg protein/10 sec versus 415 +/- 24 in septic ileum, p less than 0.001) The rate of jejunal transport of alanine, leucine, and glucose was also decreased in septic patients by 30% to 50% (p less than 0.01). These data suggest that there is a generalized down-regulation of sodium-dependent carrier-mediated substrate transport across the brush border during severe infection, which probably occurs secondary to a decrease in transporter synthesis or an increase in the rate of carrier degradation.(ABSTRACT TRUNCATED AT 400 WORDS)

Phase II study of a TLR-9 agonist (1018 ISS) with rituximab in patients with relapsed or refractory follicular lymphoma.

Toll‐like receptor‐9 (TLR‐9) agonists have pleotropic effects on both the innate and adaptive immune systems, including increased antigen expression, enhanced antibody‐dependent cell‐mediated cytotoxicity (ADCC) and T helper cell type 1 shift in the immune response. We combined a TLR‐9 agonist (1018 ISS, 0·2 mg/kg sc weekly × 4 beginning day 8) with standard rituximab (375 mg/m2 weekly × 4) in patients (n = 23) with relapsed/refractory, histologically confirmed follicular lymphoma, and evaluated immunological changes following the combination. Treatment was well‐tolerated with no significant adverse events attributable to therapy. Clinical responses were observed in 48% of patients; the overall median progression‐free survival was 9 months. Biologically relevant increases in ADCC and circulating CD‐3 positive T cells were observed in 35% and 39% of patients, respectively. Forty‐five percent of patients had increased T cells and dendritic cells in skin biopsies of 1018 ISS injection sites 24 h post‐therapy. Pre‐ and post‐biopsies of tumour tissue demonstrated an infiltration of CD8+ T cells and macrophages following treatment. This group of patients had favourable clinical outcome despite adverse prognostic factors. This study is the first to histologically confirm perturbation of the local immune microenvironment following systemic biological therapy of follicular lymphoma.

How much do we need to worry about venous thromboembolism after hospital discharge? A study of colorectal surgery patients using the National Surgical Quality Improvement Program database.

PURPOSE: It is well recognized that the increased risk of a postoperative venous thrombotic event extends beyond the inpatient treatment period. The purpose of this study was to determine the 30-day incidence and risk factors associated with the occurrence of early postdischarge symptomatic venous thromboembolic events in patients who have undergone major colorectal surgery. METHODS: The National Surgical Quality Improvement Program database was queried for patients who had undergone a colon or rectal resection during the study period (2005–2008). Patient demographics, preoperative risk factors, and operative variables were recorded. The primary outcomes were occurrence of deep venous thrombosis requiring therapy or pulmonary embolism within 30 days after initial surgery. The occurrence of postdischarge venous thromboembolic events was calculated from the days to primary outcome and days from operation to discharge. Univariate and multivariate linear regression models incorporating pre- and intraoperative variables as well as the occurrence of a major or minor complication were used to evaluate the effect of these clinical factors on the early postdischarge venous thromboembolic event rate. RESULTS: A total of 52,555 patients were included in the initial analysis. A total of 240 deep venous thromboses were diagnosed in the postdischarge setting giving a postdischarge incidence of 0.47%. One hundred thirty cases of a pulmonary embolus were diagnosed (0.26% incidence) with 30 patients having a concurrent deep venous thrombosis and pulmonary embolus. The overall cumulative postdischarge symptomatic venous thromboembolic incidence was 0.67% (n = 340). Obesity, preoperative steroid use, “bleeding disorder,” ASA class III, and postoperative (major and minor) complications were all independently associated with an increased risk of an early postdischarge venous thromboembolic event. CONCLUSION: This study has identified risk factors that may help stratify patients into different risk profiles and offer prolonged prophylaxis to patients at increased risk on the basis of preoperative risk factors and postoperative complications.

Intestinal Glutamine Metabolism after Massive Small Bowel Resection

Gut glutamine utilization after massive small bowel resection was studied to gain further insight into the alterations and adaptations in intestinal glutamine metabolism that occur during the development of post-resectional hyperplasia. After resection of the middle 60% of the small intestine in the rat, gut glutamine metabolism was studied immediately and 1, 2, and 3 weeks later. Whole gut glutamine extraction was 22% in sham controls and it acutely declined to 12% (p less than 0.01) after bowel resection. Extraction increased to 31% 1 week later (p less than 0.05) and then returned to normal by week 2. Gut ammonia release decreased after massive small bowel resection, whereas intestinal alanine release increased. The increase in gut glutamine extraction at 1 week occurred at a time when jejunal and ileal DNA and protein content were markedly increased (p less than 0.01). Intestinal glutaminase content declined initially and then increased by the third week after bowel resection (p less than 0.01). With time, increases in gut cellularity and glutaminase content are associated with gut glutamine utilization in the shortened small bowel that is equal to that of the intact unresected intestine.

Balancing the risk of postoperative surgical infections: a multivariate analysis of factors associated with laparoscopic appendectomy from the NSQIP database.

Objective: To establish the relationship between operative approach (laparoscopic or open) and subsequent surgical infection (both incisional and organ space infection) postappendectomy, independent of potential confounding factors. Background: Although laparoscopic appendectomy has been associated with lower rates of incisional infections than an open approach, the relationship between laparoscopy and organ space infection (OSI) is not as clearly established. Methods: Cases of appendectomy were retrieved from the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database for 2005 to 2008. Patient factors, operative variables, and the primary outcomes of incisional infections and OSIs were recorded. Factors associated with surgical infections were identified using logistic regression models. These models were then used to calculate probabilities of OSI in clinical vignettes demonstrating varying levels of infectious risk. Results: A total of 39,950 appendectomy cases were included of which 30,575 (77%) were performed laparoscopically. On multivariate analysis, laparoscopy was associated with a lower risk of incisional infection [odds ratio (OR) 0.37, 95% confidence interval (CI) 0.32–0.43] but with an increased risk of OSI after adjustment for confounding factors (OR 1.44, 95% CI 1.21–1.73). For a low-risk patient, probability of OSI was calculated to be 0.3% and 0.4%, respectively, for open versus laparoscopic appendectomy, whereas for a high-risk patient, probabilities were estimated at 8.9% and 12.3%, respectively. Conclusion: Laparoscopy was associated with a decreased risk of incisional infection but with an increased risk of OSI. The degree of this increased risk varies depending on the clinical profile of a surgical patient. Recognition of these differences in risk may aid clinicians in the choice of operative approach for appendectomy.