Martijn Poeze

Functional compromise reflected by sarcopenia, frailty, and nutritional depletion predicts adverse postoperative outcome after colorectal cancer surgery

OBJECTIVE To determine the association of sarcopenia with postoperative morbidity and mortality after colorectal surgery. BACKGROUND Functional compromise in elderly colorectal surgical patients is considered as a significant factor of impaired postoperative recovery. Therefore, the predictive value of preoperative functional compromise assessment was investigated. Sarcopenia is a hallmark of functional compromise. METHODS A total of 310 consecutive patients who underwent oncologic colorectal surgery were included in a prospective digital database. Sarcopenia was assessed using the L3 muscle index utilizing Osirix on preoperative computed tomography. Groningen Frailty Indicator and Short Nutritional Assessment Questionnaire scores were used to assess frailty and nutritional compromise. Predictors for anastomotic leakage, sepsis, and mortality were analyzed by logistic regression analysis. RESULTS Age was an independent predictor of mortality [P = 0.04; odds ratio, 1.17; 95% confidence interval (CI), 1.01-1.37]. Thirty-day/in-hospital mortality rate in sarcopenic patients was 8.8% versus 0.7% in nonsarcopenic patients (P = 0.001; odds ratio, 15.5; 95% CI, 2.00-120). Sarcopenia was not predictive for anastomotic leakage or sepsis. Combination of high Short Nutritional Assessment Questionnaire score, high Groningen Frailty Indicator score, and sarcopenia strongly predicted sepsis (P = 0.001; odds ratio, 25.1; 95% CI, 5.11-123), sensitivity, 46%; specificity, 97%; positive likelihood ratio, 13 (95% CI, 4.4-38); negative likelihood ratio, 0.57 (95% CI, 0.33-0.97). CONCLUSIONS Functional compromise in colorectal cancer surgery is associated with adverse postoperative outcome. Assessment of functional compromise by means of a nutritional questionnaire (Short Nutritional Assessment Questionnaire), a frailty questionnaire (Groningen Frailty Indicator), and sarcopenia measurement (L3 muscle index) can accurately predict postoperative sepsis.

Sepsis: an arginine deficiency state?

Objective:Sepsis is a major health problem considering its significant morbidity and mortality rate. The amino acid l-arginine has recently received substantial attention in relation to human sepsis. However, knowledge of arginine metabolism during sepsis is limited. Therefore, we reviewed the current knowledge about arginine metabolism in sepsis. Data Source:This review summarizes the literature on arginine metabolism both in general and in relation to sepsis. Moreover, arginine-related therapies are reviewed and discussed, which includes therapies of both nitric oxide (NO) and arginine administration and therapies directed toward inhibition of NO. Data:In sepsis, protein breakdown is increased, which is a key process to maintain arginine delivery, because both endogenous de novo production from citrulline and food intake are reduced. Arginine catabolism, on the other hand, is markedly increased by enhanced use of arginine in the arginase and NO pathways. As a result, lowered plasma arginine levels are usually found. Clinical symptoms of sepsis that are related to changes in arginine metabolism are mainly related to hemodynamic alterations and diminished microcirculation. NO administration and arginine supplementation as a monotherapy demonstrated beneficial effects, whereas nonselective NO synthase inhibition seemed not to be beneficial, and selective NO synthase 2 inhibition was not beneficial overall. Conclusions:Because sepsis has all the characteristics of an arginine-deficiency state, we hypothesise that arginine supplementation is a logical option in the treatment of sepsis. This is supported by substantial experimental and clinical data on NO donors and NO inhibitors. However, further evidence is required to prove our hypothesis.

Meta-analysis of hemodynamic optimization: relationship to methodological quality

IntroductionTo review systematically the effect of interventions aimed at hemodynamic optimization and to relate this to the quality of individual published trials.MethodsA systematic, computerized bibliographic search of published studies and citation reviews of relevant studies was performed. All randomized clinical trials in which adult patients were included in a trial deliberately aiming at an optimized or maximized hemodynamic condition of the patients (with oxygen delivery, cardiac index, oxygen consumption, mixed venous oxygen saturation and/or stroke volume as end-points) were selected. A total of 30 studies were selected for independent review. Two reviewers extracted data on population, intervention, outcome and methodological quality. Agreement between reviewers was high: differences were eventually resolved by third-party decision. The methodological quality of the studies was moderate (mean 9.0, SD 1.7), and the outcomes of the randomized clinical trials were not related to their quality.ResultsEfforts to achieve an optimized hemodynamic condition resulted in a decreased mortality rate (relative risk ratio (RR) 0.75 (95% confidence interval (CI) 0.62 to 0.90) in all studies combined. This was due to a significantly decreased mortality in peri-operative intervention studies (RR 0.66 (95% CI 0.54 to 0.81). Overall, patients with sepsis and overt organ failure do not benefit from this method (RR 0.92 (95% CI 0.75 to 1.11)).ConclusionThis systematic review showed that interventions aimed at hemodynamic optimization reduced mortality. In particular, trials including peri-operative interventions aimed at the hemodynamic optimization of high-risk surgical patients reduce mortality. Overall, this effect was not related to the trial quality.

Early Diagnosis of Intestinal Ischemia Using Urinary and Plasma Fatty Acid Binding Proteins

OBJECTIVE This study aims at improving diagnosis of intestinal ischemia, by measuring plasma and urinary fatty acid binding protein (FABP) levels. METHODS Fifty consecutive patients suspected of intestinal ischemia were included and blood and urine were sampled at time of suspicion. Plasma and urinary concentrations of intestinal FABP (I-FABP), liver FABP (L-FABP) and ileal bile acid binding protein (I-BABP) were measured using enzyme-linked immunosorbent assays. RESULTS Twenty-two patients suspected of intestinal ischemia were diagnosed with intestinal ischemia, 24 patients were diagnosed with other diseases, and 4 patients were excluded from further analysis fulfilling exclusion criteria. Median plasma concentrations of I-FABP and L-FABP and urinary concentrations of all 3 markers were significantly higher in patients with proven intestinal ischemia than in patients suspected of intestinal ischemia with other final diagnoses (plasma I-FABP; 653 pg/mL vs. 109 pg/mL, P = 0.02, plasma L-FABP; 117 ng/mL vs. 25 ng/mL, P = 0.006, urine I-FABP; 3377 pg/mL vs. 115 pg/mL, P = 0.001, urine L-FABP; 1,199 ng/mL vs. 37 ng/mL, P =0.004, urine I-BABP; 48.6 ng/mL vs. 0.6 ng/mL, P = 0.002). Positive and negative likelihood ratios significantly increased positive posttest probability and decreased negative posttest probability on intestinal ischemia. In patients with intestinal ischemia a trend to higher plasma I-BABP levels was observed when the ileum was involved (18.4 ng/mL vs. 2.9 ng/mL, P = 0.05). CONCLUSION Plasma and especially urinary I-FABP and L-FABP levels and urinary I-BABP levels can improve early diagnosis of intestinal ischemia. Furthermore, plasma I-BABP levels can help in localizing ileal ischemia.

Evidence for intestinal and liver epithelial cell injury in the early phase of sepsis

The development of sepsis and multiple organ failure are important determinants of the outcome in critically ill patients. Hepatosplanchnic hypoperfusion and resulting intestinal and hepatic cell damage have been implicated as central events in the development of sepsis and multiple organ failure. Our aim was to study (1) the relation between intramucosal perfusion and intestinal and hepatic cell damage in an early phase of sepsis and (2) the correlation of these parameters with mortality. Two groups of patients were consecutively selected after intensive care unit admission: patients with postoperative abdominal sepsis (n = 19) and patients with pneumonia-induced sepsis (n = 9). Intramucosal perfusion was assessed by gastric tonometry (Pr-aco2 gap, Pico2). Circulating levels of intestinal fatty acid binding protein (I-FABP) and liver (L)-FABP were used as markers for intestinal and hepatic cellular damage, respectively. Outcome was determined on day 28. Pr-aco2 gap correlated with I-FABP (Pearson r2 = 0.56; P < 0.001) in all patients, and gastric mucosal Pico2 correlated significantly with I-FABP (r2 = 0.57; P = 0.001) in patients with abdominal sepsis. At intensive care unit admission, nonsurvivors had significantly higher I-FABP and L-FABP values than survivors (I-FABP: 325 vs. 76 pg/mL, P < 0.04; L-FABP: 104 vs. 31 ng/mL, P < 0.04). Patients with abdominal sepsis was especially responsible for high-admission I-FABP and L-FABP levels in nonsurvivors (I-FABP: 405 vs. 85 pg/mL, P < 0.04; L-FABP: 121 vs. 59 ng/mL, P < 0.04). This study shows that splanchnic hypoperfusion correlates with intestinal mucosal damage, and that elevated plasma levels of I-FABP and L-FABP are associated with a poor outcome in critically ill patients with abdominal sepsis.

The Role of Arginine in Infection and Sepsis

Sepsis is a systemic response to an infection, with high morbidity and mortality rates. Metabolic changes during infection and sepsis could be related to changes in metabolism of the amino acid L-arginine. In sepsis, protein breakdown is increased, which is a key process to maintain arginine delivery because both endogenous de novo arginine production from citrulline and food intake are reduced. Arginine catabolism, on the other hand, is markedly increased by enhanced use of arginine via the arginase and nitric oxide pathways. As a result, lowered plasma arginine levels are usually found. Arginine may therefore be considered as an essential amino acid in sepsis, and supplementation could be beneficial in sepsis by improving microcirculation and protein anabolism. L-Arginine supplementation in a hyperdynamic pig model of sepsis prohibits the increase in pulmonary arterial blood pressure, improves muscle and liver protein metabolism, and restores the intestinal motility pattern. Arguments raised against arginine supplementation are mainly pointed at stimulating nitric oxide (NO) production, with concerns about toxicity of increased NO and hemodynamic instability with refractory hypotension. NO synthase inhibition, however, increased mortality. Arginine supplementation in septic patients has transient effects on hemodynamics when supplied as a bolus but seems without hemodynamic side effects when supplied continuously. In conclusion, arginine could have an essential role in infection and sepsis.

Physiology and pathophysiology of splanchnic hypoperfusion and intestinal injury during exercise: strategies for evaluation and prevention

Physical exercise places high demands on the adaptive capacity of the human body. Strenuous physical performance increases the blood supply to active muscles, cardiopulmonary system, and skin to meet the altered demands for oxygen and nutrients. The redistribution of blood flow, necessary for such an increased blood supply to the periphery, significantly reduces blood flow to the gut, leading to hypoperfusion and gastrointestinal (GI) compromise. A compromised GI system can have a negative impact on exercise performance and subsequent postexercise recovery due to abdominal distress and impairments in the uptake of fluid, electrolytes, and nutrients. In addition, strenuous physical exercise leads to loss of epithelial integrity, which may give rise to increased intestinal permeability with bacterial translocation and inflammation. Ultimately, these effects can deteriorate postexercise recovery and disrupt exercise training routine. This review provides an overview on the recent advances in our understanding of GI physiology and pathophysiology in relation to strenuous exercise. Various approaches to determine the impact of exercise on the individual athletes GI tract are discussed. In addition, we elaborate on several promising components that could be exploited for preventive interventions.

Citrulline a more suitable substrate than arginine to restore NO production and the microcirculation during endotoxemia

Background Impaired microcirculation during endotoxemia correlates with a disturbed arginine-nitric oxide (NO) metabolism and is associated with deteriorating organ function. Improving the organ perfusion in endotoxemia, as often seen in patients with severe infection or systemic inflammatory response syndrome (SIRS) is, therefore, an important therapeutic target. We hypothesized that supplementation of the arginine precursor citrulline rather than arginine would specifically increase eNOS-induced intracellular NO production and thereby improve the microcirculation during endotoxemia. Methodology/Principal Findings To study the effects of L-Citrulline and L-Arginine supplementation on jejunal microcirculation, intracellular arginine availability and NO production in a non-lethal prolonged endotoxemia model in mice. C57/Bl6 mice received an 18 hrs intravenous infusion of endotoxin (LPS, 0.4 µg•g bodyweight−1•h−1), combined with either L-Citrulline (6.25 mg•h-1), L-Arginine (6.25 mg•h−1), or L-Alanine (isonitrogenous control; 12.5 mg•h−1) during the last 6 hrs. The control group received an 18 hrs sterile saline infusion combined with L-Alanine or L-Citrulline during the last 6 hrs. The microcirculation was evaluated at the end of the infusion period using sidestream dark-field imaging of jejunal villi. Plasma and jejunal tissue amino-acid concentrations were measured by HPLC, NO tissue concentrations by electron-spin resonance spectroscopy and NOS protein concentrations using Western blot. Conclusion/Significance L-Citrulline supplementation during endotoxemia positively influenced the intestinal microvascular perfusion compared to L-Arginine-supplemented and control endotoxemic mice. L-Citrulline supplementation increased plasma and tissue concentrations of arginine and citrulline, and restored intracellular NO production in the intestine. L-Arginine supplementation did not increase the intracellular arginine availability. Jejunal tissues in the L-Citrulline-supplemented group showed, compared to the endotoxemic and L-Arginine-supplemented endotoxemic group, an increase in degree of phosphorylation of eNOS (Ser 1177) and a decrease in iNOS protein level. In conclusion, L-Citrulline supplementation during endotoxemia and not L-Arginine reduced intestinal microcirculatory dysfunction and increased intracellular NO production, likely via increased intracellular citrulline and arginine availability.

An international survey: Public awareness and perception of sepsis

Background:Sepsis is a common cause of death throughout the world. Early treatment improves outcome; however, treatment may be delayed if the patient does not present himself/herself for medical care until late in the disease process. Lack of knowledge about the syndrome may contribute to delay in presenting for medical care. However, we need to acknowledge the complexity of sepsis. General awareness of sepsis by the public may increase political pressure for research funding. Increased public awareness of acute myocardial infarction has contributed to reduced mortality over the last 50 yrs. This example provides a rationale for future efforts to increase the public awareness of sepsis. Objective:The survey was designed to gain insight into public perceptions and attitudes regarding sepsis. Design:Prospective, international survey performed using structured telephone interviews. Subjects:A total of 6021 interviewees, 5021 in Europe and 1000 in the United States. Measurements and Main Results:In Italy, Spain, the United Kingdom, France and the United States, a mean of 88% of interviewees had never heard of the term “sepsis”. In Germany 53% of people knew the word sepsis. In Italy, Spain, United Kingdom, France, and United States, of people who recognized the term sepsis, 58% did not recognize that sepsis is a leading cause of death. Conclusions:There is poor public awareness about the existence of a syndrome known as sepsis. Results of this questionnaire underscore the challenges in early management and treatment of infected patients at risk for developing sepsis syndrome.

New Insight in Loss of Gut Barrier during Major Non-Abdominal Surgery.

Background Gut barrier loss has been implicated as a critical event in the occurrence of postoperative complications. We aimed to study the development of gut barrier loss in patients undergoing major non-abdominal surgery. Methodology/Principal Findings Twenty consecutive children undergoing spinal fusion surgery were included. This kind of surgery is characterized by long operation time, significant blood loss, prolonged systemic hypotension, without directly leading to compromise of the intestines by intestinal manipulation or use of extracorporeal circulation. Blood was collected preoperatively, every two hours during surgery and 2, 4, 15 and 24 hours postoperatively. Gut mucosal barrier was assessed by plasma markers for enterocyte damage (I-FABP, I-BABP) and urinary presence of tight junction protein claudin-3. Intestinal mucosal perfusion was measured by gastric tonometry (PrCO2, Pr-aCO2-gap). Plasma concentration of I-FABP, I-BABP and urinary expression of claudin-3 increased rapidly and significantly after the onset of surgery in most children. Postoperatively, all markers decreased promptly towards baseline values together with normalisation of MAP. Plasma levels of I-FABP, I-BABP were significantly negatively correlated with MAP at ½ hour before blood sampling (−0.726 (p<0.001), −0.483 (P<0.001), respectively). Furthermore, circulating I-FABP correlated with gastric mucosal PrCO2, Pr-aCO2-gap measured at the same time points (0.553 (p = 0.040), 0.585 (p = 0.028), respectively). Conclusions/Significance This study shows the development of gut barrier loss in children undergoing major non-abdominal surgery, which is related to preceding hypotension and mesenterial hypoperfusion. These data shed new light on the potential role of peroperative circulatory perturbation and intestinal barrier loss.