Kostan W. Reisinger

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.

Noninvasive measurement of fecal calprotectin and serum amyloid A combined with intestinal fatty acid–binding protein in necrotizing enterocolitis

BACKGROUND Diagnosis of necrotizing enterocolitis (NEC), prevalent in premature infants, remains challenging. Enterocyte damage in NEC can be assessed by intestinal fatty acid-binding protein (I-FABP), with a sensitivity of 93% and a specificity of 90%. Numerous markers of inflammation are known, such as serum amyloid A (SAA) and fecal calprotectin. PURPOSE The aim of the present study was to evaluate which combination of noninvasive measurement of inflammatory markers and I-FABP improves the diagnostic accuracy in neonates suspected for NEC. METHODS In 62 neonates with clinical suspicion of NEC (29 with final diagnosis of NEC), urinary I-FABP, urinary SAA, and fecal calprotectin levels were determined quantitatively. Diagnostic accuracy was calculated for the combinations I-FABP-SAA and I-FABP-fecal calprotectin, using a multivariable logistic regression model. RESULTS The combination of SAA and I-FABP did not increase the diagnostic accuracy of I-FABP. However, the combination of fecal calprotectin and I-FABP improved accuracy significantly. The combination of urinary I-FABP and fecal calprotectin measurement produced a sensitivity of 94%, a specificity of 79%, a positive likelihood ratio of 4.48, and a negative likelihood ratio of 0.08. CONCLUSION The combination of noninvasive measurement of I-FABP and fecal calprotectin seems promising for diagnosing NEC at an early time point. Prospective analysis is required to confirm this finding and to evaluate better treatment strategies based on noninvasive measurement of I-FABP and calprotectin.

Protection against early intestinal compromise by lipid-rich enteral nutrition through cholecystokinin receptors.

Objective:Early gut wall integrity loss and local intestinal inflammation are associated with the development of inflammatory complications in surgical and trauma patients. Prevention of these intestinal events is a potential target for therapies aimed to control systemic inflammation. Previously, we demonstrated in a rodent shock model that lipid-rich enteral nutrition attenuated systemic inflammation and prevented organ damage through a cholecystokinin receptor-dependent vagal pathway. The influence of lipid-rich nutrition on very early intestinal compromise as seen after shock is investigated. Next, the involvement of cholecystokinin receptors on the nutritional modulation of immediate gut integrity loss and intestinal inflammation is studied. Design:Randomized controlled in vivo study. Setting:University research unit. Subjects:Male Sprague-Dawley rats. Interventions:Liquid lipid-rich nutrition or control low-lipid feeding was administered per gavage before hemorrhagic shock. Cholecystokinin receptor antagonists were used to investigate involvement of the vagal antiinflammatory pathway. Measurements and Main Results:Gut permeability to horseradish peroxidase increased as soon as 30 mins postshock and was prevented by lipid-rich nutrition compared with low-lipid (p < .01) and fasted controls (p < .001). Furthermore, lipid-rich nutrition reduced plasma levels of enterocyte damage marker ileal lipid binding protein at 60 mins (p < .05). Early gut barrier dysfunction correlated with rat mast cell protease plasma concentrations at 30 mins (rs = 0.67; p < .001) and intestinal myeloperoxidase levels at 60 mins (rs = 0.58; p < .05). Lipid-rich nutrition significantly reduced plasma rat mast cell protease (p < .01) and myeloperoxidase (p < .05) before systemic inflammation was detectable. Protective effects of lipid-rich nutrition were abrogated by cholecystokinin receptor antagonists (horseradish peroxidase; p < .05 and rat mast cell protease; p < .05). Conclusions:Lipid-rich enteral nutrition prevents early gut barrier loss, enterocyte damage, and local intestinal inflammation before systemic inflammation develops in a cholecystokinin receptor-dependent manner. This study identifies activation of the vagal antiinflammatory pathway with lipid-rich nutrition as a potential therapy in patients prone to develop a compromised gut.

Sarcopenia negatively affects preoperative total functional liver volume in patients undergoing liver resection.

OBJECTIVES Sarcopenia may negatively affect short-term outcomes after liver resection. The present study aimed to explore whether total functional liver volume (TFLV) is related to sarcopenia in patients undergoing partial liver resection. METHODS Analysis of total liver volume and tumour volume and measurements of muscle surface were performed in patients undergoing liver resection using OsiriX(®) and preoperative computed tomography. The ratio of TFLV to bodyweight was calculated as: [TFLV (ml)/bodyweight (g)]*100%. The L3 muscle index (cm(2) /m(2) ) was then calculated by normalizing muscle areas (at the third lumbar vertebral level) for height. RESULTS Of 40 patients, 27 (67.5%) were classified as sarcopenic. There was a significant correlation between the L3 skeletal muscle index and TFLV (r= 0.64, P < 0.001). Median TFLV was significantly lower in the sarcopenia group than in the non-sarcopenia group [1396 ml (range: 1129-2625 ml) and 1840 ml (range: 867-2404 ml), respectively; P < 0.05]. Median TFLV : bodyweight ratio was significantly lower in the sarcopenia group than in the non-sarcopenia group [2.0% (range: 1.4-2.5%) and 2.3% (range: 1.5-2.5%), respectively; P < 0.05]. CONCLUSIONS Sarcopenic patients had a disproportionally small preoperative TFLV compared with non-sarcopenic patients undergoing liver resection. The preoperative hepatic physiologic reserve may therefore be smaller in sarcopenic patients.

Accurate prediction of anastomotic leakage after colorectal surgery using plasma markers for intestinal damage and inflammation

BACKGROUND Anastomotic leakage is a frequent and life-threatening complication after colorectal surgery. Early recognition of anastomotic leakage is critical to reduce mortality. Because early clinical and radiologic signs of anastomotic leakage are often nonspecific, there is an urgent need for accurate biomarkers. Markers of inflammation and gut damage might be suitable, as these are hallmarks of anastomotic leakage. STUDY DESIGN In 84 patients undergoing scheduled colorectal surgery with primary anastomosis, plasma samples were collected preoperatively and daily after surgery. Inflammatory markers, C-reactive protein; calprotectin; and interleukin-6, and intestinal damage markers, intestinal fatty acid binding protein; liver fatty acid binding protein; and ileal bile acid binding protein, were measured. Diagnostic accuracy of single markers or combinations of markers was analyzed by receiver operating characteristic curve analysis. RESULTS Anastomotic leakage developed in 8 patients, clinically diagnosed at median day 6. Calprotectin had best diagnostic accuracy to detect anastomotic leakage postoperatively. Highest diagnostic accuracy was obtained when C-reactive protein and calprotectin were combined at postoperative day 3, yielding sensitivity of 100%, specificity of 89%, positive likelihood ratio = 9.09 (95% CI, 4.34-16), and negative likelihood ratio = 0.00 (95% CI, 0.00-0.89) (p < 0.001). Interestingly, preoperative intestinal fatty acid binding protein levels predicted anastomotic leakage at a cutoff level of 882 pg/mL with sensitivity of 50%, specificity of 100%, positive likelihood ratio = infinite (95% CI, 4.01-infinite), and negative likelihood ratio = 0.50 (95% CI, 0.26-0.98) (p < 0.0001). CONCLUSIONS Preoperative intestinal fatty acid binding protein measurement can be used for anastomotic leakage risk assessment. In addition, the combination of C-reactive protein and calprotectin has high diagnostic accuracy. Implementation of these markers in daily practice deserves additional investigation.

Total intermittent Pringle maneuver during liver resection can induce intestinal epithelial cell damage and endotoxemia.

Objectives The intermittent Pringle maneuver (IPM) is frequently applied to minimize blood loss during liver transection. Clamping the hepatoduodenal ligament blocks the hepatic inflow, which leads to a non circulating (hepato)splanchnic outflow. Also, IPM blocks the mesenteric venous drainage (as well as the splenic drainage) with raising pressure in the microvascular network of the intestinal structures. It is unknown whether the IPM is harmful to the gut. The aim was to investigate intestinal epithelial cell damage reflected by circulating intestinal fatty acid binding protein levels (I-FABP) in patients undergoing liver resection with IPM. Methods Patients who underwent liver surgery received total IPM (total-IPM) or selective IPM (sel-IPM). A selective IPM was performed by selectively clamping the right portal pedicle. Patients without IPM served as controls (no-IPM). Arterial blood samples were taken immediately after incision, ischemia and reperfusion of the liver, transection, 8 hours after start of surgery and on the first post-operative day. Results 24 patients (13 males) were included. 7 patients received cycles of 15 minutes and 5 patients received cycles of 30 minutes of hepatic inflow occlusion. 6 patients received cycles of 15 minutes selective hepatic occlusion and 6 patients underwent surgery without inflow occlusion. Application of total-IPM resulted in a significant increase in I-FABP 8 hours after start of surgery compared to baseline (p<0.005). In the no-IPM group and sel-IPM group no significant increase in I-FABP at any time point compared to baseline was observed. Conclusion Total-IPM in patients undergoing liver resection is associated with a substantial increase in arterial I-FABP, pointing to intestinal epithelial injury during liver surgery. Trial Registration ClinicalTrials.gov NCT01099475

Noninvasive measurement of intestinal epithelial damage at time of refeeding can predict clinical outcome after necrotizing enterocolitis

Background:Reintroduction of enteral nutrition in neonates with necrotizing enterocolitis (NEC) should take place when the gut is ready for its normal function. Too early a start of oral feeding might lead to disease relapse, whereas prolonged discontinuation of enteral nutrition is associated with impaired gut function and parenteral nutrition–related complications. This study evaluated whether noninvasive urinary measurement of intestinal fatty acid binding protein (I-FABP) at the time of refeeding can predict clinical outcome in neonates with NEC.Methods:Urinary I-FABP concentrations were measured in 21 infants with NEC just before reintroducing enteral nutrition. Poor outcome was defined as unsuccessful reintroduction of enteral feeding (EF), (re)operation for NEC, or death related to NEC after reintroduction of EF.Results:Median urinary I-FABP levels in neonates with poor outcome (n = 5) were significantly higher as compared with I-FABP levels in neonates with good outcome (n = 16) (P < 0.01). A clinically significant cutoff value of 963 pg/ml was found to discriminate between infants with poor outcome and those with good outcome (sensitivity 80%, specificity 94%).Conclusion:Noninvasive urinary I-FABP measurement at time of refeeding differentiates neonates with poor outcome from neonates with good outcome in NEC. Urinary I-FABP measurement may therefore be helpful in the timing of EF in neonates with NEC.

Improving the outcomes in oncological colorectal surgery

During the last several decades, colorectal cancer surgery has experienced some major perioperative improvements. Preoperative risk-assessment of nutrition, frailty, and sarcopenia followed by interventions for patient optimization or an adapted surgical strategy, contributed to improved postoperative outcomes. Enhanced recovery programs or fast-track surgery also resulted in reduced length of hospital stay and overall complications without affecting patient safety. After an initially indecisive start due to uncertainty about oncological safety, the most significant improvement in intraoperative care was the introduction of laparoscopy. Laparoscopic surgery for colon and rectal cancer is associated with better short-term outcomes, whereas long-term outcomes regarding survival and recurrence rates are comparable. Nevertheless, long-term results in rectal surgery remain to be seen. Early recognition of anastomotic leakage remains a challenge, though multiple improvements have allowed better management of this complication.

Breast-Feeding Improves Gut Maturation Compared With Formula Feeding in Preterm Babies

Objective: The incidence of necrotizing enterocolitis (NEC) is higher in formula-fed babies than in breast-fed babies, which may be caused by breast-feeding–induced gut maturation. The effect of breast-feeding on gut maturation has been widely studied in animal models. This study aimed to assess the effects of breast-feeding on intestinal maturation in prematurely born babies by evaluating postnatal changes in urinary intestinal fatty acid binding protein (I-FABP) levels, a specific enterocyte marker. Methods: Gut maturation in 40 premature babies (<37 weeks of gestation) without gastrointestinal morbidity was studied, of whom 21 were exclusively breast-fed and 19 were formula-fed infants. Urinary I-FABP levels as the measure of gut maturation were measured at 5, 12, 19, and 26 days after birth. Results: In breast-fed infants, there was a significant increase in median urinary I-FABP levels between 5 and 12 days after birth (104 [78–340] pg/mL to 408 [173–1028] pg/mL, P = 0.002), whereas I-FABP concentration in formula-fed infants increased between 12 and 19 days after birth (105 [44–557] pg/mL, 723 [103–1670] pg/mL, P = 0.004). Breast-fed babies had significantly higher median urinary I-FABP levels at postnatal day 12 (P = 0.01). Conclusions: The time course of the postnatal increase in urinary I-FABP levels reflecting gut maturation was significantly delayed in formula-fed babies, suggesting a delayed physiological response in formula-fed compared with breast-fed infants.

Intestinal fatty acid-binding protein: a possible marker for gut maturation

Background:Gut immaturity is linked with postnatal intestinal disorders. However, biomarkers to assess the intestinal developmental stage around birth are lacking. The aim of this study was to gain more insight on intestinal fatty acid–binding protein (I-FABP) as an indicator of gut maturity.Methods:Antenatal I-FABP distribution and release was investigated in extremely premature, moderately premature, and term lambs, and these findings were verified in human urinary samples. Ileal I-FABP distribution was confirmed in autopsy material within 24 h postnatally.Results:Median (range) serum I-FABP levels were lower in extremely premature lambs compared with moderately premature lambs (156 (50.0–427) vs. 385 (100–1,387) pg/ml; P = 0.02). Contrarily, median early postnatal urine I-FABP levels in human infants were higher in extremely premature compared with moderately premature and term neonates (1,219 (203–15,044) vs. 256 (50–1,453) and 328 (96–1,749) pg/ml; P = 0.008 and P = 0.04, respectively). I-FABP expression was most prominent in nonvacuolated enterocytes and increased with rising gestational age (GA) in ovine and human tissue samples. The epithelial distribution pattern changed from a phenotype displaying I-FABP-positive enterocytes merely in the crypts early in gestation into a phenotype with I-FABP expressing cells exclusively present in the villus tips at term in ovine and human tissue.Conclusion:In this ovine and human study, increasing GA is accompanied by an increase in I-FABP tissue content. Cord I-FABP levels correlate with gestation in ovine fetuses, identifying I-FABP as a marker for gut maturation. Raised postnatal urine I-FABP levels in preterm human infants may indicate intestinal injury and/or inflammation in utero.Pediatric Research (2014); 76 3, 261–268. doi:10.1038/pr.2014.89