Erik Heineman

Somatic and psychologic predictors of long-term unfavorable outcome after surgical intervention

Objective:To identify somatic and psychologic predictors of pain, functional limitations, global perceived recovery, and quality of life 6 months after surgical intervention. Summary Background Data:Recent studies have indicated that chronic pain after surgical intervention is more common than previously assumed. Several demographic and somatic predictors of long-term unfavorable outcome have been identified, but little is known about the contribution of psychologic risk factors. Methods:A prospective cohort study, including 625 patients undergoing elective surgery at the University Hospital Maastricht, The Netherlands, was conducted between February and August 2003. Psychologic questionnaires were completed preoperatively and acute postoperative pain was recorded until 4 days after the operation. Six months later, all patients received follow-up questionnaires to assess pain, functional limitations, global perceived recovery, and quality of life. Multivariable logistic regression analyses were used to estimate relative risk of poor outcome in terms of pain, functional limitations, and global recovery. Multivariable linear regression analysis was used to assess associations with quality of life at 6 months. Results:The most important somatic predictors of unfavorable outcome were duration of the operation and high levels of acute postoperative pain. Patients reporting high levels of pain 4 days after the operation and patients undergoing an operation of longer than 3 hours were at risk for increased pain, increased functional limitations, poor global recovery, and reported lower levels of quality of life 6 months after the operation. Psychologic variables that influenced long-term outcome were preoperative fear of surgery and optimism. Fear of the long-term consequences of the operation was associated with more pain, poor global recovery, and worse quality of life 6 months later, whereas optimism was associated with better recovery and higher quality of life. Conclusions:This study was the first to identify the joint contribution of somatic and psychologic factors to chronic pain, functional limitations, and quality of life 6 months after surgical interventions. It replicates previous findings that intense acute postoperative pain is a risk factor for long-term adverse outcome and also identified additional risk factors, namely, long duration of the operation, ASA status, and preoperative fear of surgery.

Effect of Dietary Inulin Supplementation on Inflammation of Pouch Mucosa in Patients With an Ileal Pouch-Anal Anastomosis

AbstractPURPOSE: Inflammation is a constant finding in the ileal reservoir of patients with an ileal pouch-anal anastomosis and is associated with decreased fecal concentrations of the short chain fatty acid butyrate, increased fecal pH, changes in fecal flora, and increased concentrations of secondary bile acids. In healthy subjects, inulin, a dietary fiber, is fermented to short chain fatty acids and leads to a lower pH and potentially beneficial changes in fecal flora. The aim of the present study was to investigate the effect of enteral supplementation of inulin on inflammation of the ileal reservoir. METHODS: Twenty patients received 24 g of inulin or placebo daily during three weeks in a randomized, double-blind, crossover design. Stools were analyzed after each test period for pH, short chain fatty acids, microflora, and bile acids. Inflammation was assessed endoscopically, histologically, and clinically. RESULTS: Compared with placebo, three weeks of dietary supplementation with 24 g of inulin increased butyrate concentrations, lowered pH, decreased numbers of Bacteroides fragilis, and diminished concentrations of secondary bile acids in feces. This was endoscopically and histologically accompanied by a reduction of inflammation of the mucosa of the ileal reservoir. CONCLUSION: Enteral inulin supplementation leads to a decrease of inflammation-associated factors and to a reduction of inflammation of pouch mucosa.

Non-Invasive Markers for Early Diagnosis and Determination of the Severity of Necrotizing Enterocolitis

Objectives:To improve diagnosis of necrotizing enterocolitis (NEC) by noninvasive markers representing gut wall integrity loss (I-FABP and claudin-3) and gut wall inflammation (calprotectin). Furthermore, the usefulness of I-FABP to predict NEC severity and to screen for NEC was evaluated. Methods:Urinary I-FABP and claudin-3 concentrations and fecal calprotectin concentrations were measured in 35 consecutive neonates suspected of NEC at the moment of NEC suspicion. To investigate I-FABP as screening tool for NEC, daily urinary levels were determined in 6 neonates who developed NEC out of 226 neonates included before clinical suspicion of NEC. Results:Of 35 neonates suspected of NEC, 14 developed NEC. Median I-FABP, claudin-3, and calprotectin levels were significantly higher in neonates with NEC than in neonates with other diagnoses. Cutoff values for I-FABP (2.20 pg/nmol creatinine), claudin-3 (800.8 INT), and calprotectin (286.2 &mgr;g/g feces) showed clinically relevant positive likelihood ratios (LRs) of 9.30, 3.74, 12.29, and negative LRs of 0.08, 0.36, 0.15, respectively. At suspicion of NEC, median urinary I-FABP levels of neonates with intestinal necrosis necessitating surgery or causing death were significantly higher than urinary I-FABP levels in conservatively treated neonates.Of the 226 neonates included before clinical suspicion of NEC, 6 developed NEC. In 4 of these 6 neonates I-FABP levels were not above the cutoff level to diagnose NEC before clinical suspicion. Conclusions:Urinary I-FABP levels are not suitable as screening tool for NEC before clinical suspicion. However, urinary I-FABP and claudin-3 and fecal calprotectin are promising diagnostic markers for NEC. Furthermore, urinary I-FABP might also be used to predict disease severity.

Postoperative cognitive dysfunction: Involvement of neuroinflammation and neuronal functioning.

Postoperative cognitive dysfunction (POCD) has been hypothesized to be mediated by surgery-induced inflammatory processes, which may influence neuronal functioning either directly or through modulation of intraneuronal pathways, such as the brain derived neurotrophic factor (BDNF) mediated pathway. To study the time course of post-surgical (neuro)inflammation, changes in the BDNF-pathway and POCD, we subjected 3months old male Wistar rats to abdominal surgery and implanted a jugular vein catheter for timed blood sampling. Cognition, affective behavior and markers for (neuro)inflammation, BDNF and neurogenesis were assessed at 1, 2 and 3weeks following surgery. Rats displayed changes in exploratory activity shortly after surgery, associated with postoperatively elevated IL-6 plasma levels. Spatial learning and memory were temporarily impaired in the first 2weeks following surgery, whereas non-spatial cognitive functions seemed unaffected. Analysis of brain tissue revealed increased neuroinflammation (IL-1B and microgliosis) 7days following surgery, decreased BDNF levels on postoperative day 14 and 21, and decreased neurogenesis until at least 21days following surgery. These findings indicate that in young adult rats only spatial learning and memory is affected by surgery, suggesting hippocampal dependent cognition is especially vulnerable to surgery-induced impairment. The observed differences in time course following surgery and relation to plasma IL-6 suggest cognitive dysfunction and mood changes comprise distinct features of postoperative behavioral impairment. The postoperative changes in neuroinflammation, BDNF and neurogenesis may represent aspects of the underlying mechanism for POCD. Future research should be aimed to elucidate how these players interact.

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.

Rapid Reversal of Human Intestinal Ischemia-Reperfusion Induced Damage by Shedding of Injured Enterocytes and Reepithelialisation

Background Intestinal ischemia-reperfusion (IR) is a phenomenon related to physiological conditions (e.g. exercise, stress) and to pathophysiological events (e.g. acute mesenteric ischemia, aortic surgery). Although intestinal IR has been studied extensively in animals, results remain inconclusive and data on human intestinal IR are scarce. Therefore, an experimental harmless model for human intestinal IR was developed, enabling us to clarify the sequelae of human intestinal IR for the first time. Methods and Findings In 30 patients undergoing pancreatico-duodenectomy we took advantage of the fact that in this procedure a variable length of jejunum is removed. Isolated jejunum (5 cm) was subjected to 30 minutes ischemia followed by reperfusion. Intestinal Fatty Acid Binding Protein (I-FABP) arteriovenous concentration differences across the bowel segment were measured before and after ischemia to assess epithelial cell damage. Tissue sections were collected after ischemia and at 25, 60 and 120 minutes reperfusion and stained with H&E, and for I-FABP and the apoptosis marker M30. Bonferronis test was used to compare I-FABP differences. Mean (SEM) arteriovenous concentration gradients of I-FABP across the jejunum revealed rapidly developing epithelial cell damage. I-FABP release significantly increased from 290 (46) pg/ml before ischemia towards 3,997 (554) pg/ml immediately after ischemia (p<0.001) and declined gradually to 1,143 (237) pg/ml within 1 hour reperfusion (p<0.001). Directly after ischemia the intestinal epithelial lining was microscopically normal, while subepithelial spaces appeared at the villus tip. However, after 25 minutes reperfusion, enterocyte M30 immunostaining was observed at the villus tip accompanied by shedding of mature enterocytes into the lumen and loss of I-FABP staining. Interestingly, within 60 minutes reperfusion the epithelial barrier resealed, while debris of apoptotic, shedded epithelial cells was observed in the lumen. At the same time, M30 immunoreactivity was absent in intact epithelial lining. Conclusions This is the first human study to clarify intestinal IR induced cell damage and repair and its direct consequences. It reveals a unique, endogenous clearing mechanism for injured enterocytes: rapid detachment of damaged apoptotic enterocytes into the lumen. This process is followed by repair of the epithelial continuity within an hour, resulting in a normal epithelial lining.

Urine based detection of intestinal mucosal cell damage in neonates with suspected necrotising enterocolitis

Necrotising enterocolitis (NEC) is a severe gastrointestinal disease with a mortality of 20–40%, affecting predominantly premature neonates.1 In the early phase of the disease NEC continues to present a diagnostic challenge for the attending clinician. The signs and symptoms are often non-specific, including gastrointestinal problems such as abdominal distension and feeding intolerance, which are also among the most prevalent presenting features of neonatal sepsis.2 The diagnosis is further hampered by the limited diagnostic accuracy of the laboratory and radiological tests currently in use.3,4 Histopathologically, NEC is characterised by intestinal coagulative or ischaemic necrosis, starting at the mucosa and extending into the submucosa and muscularis externa.1 We sought a non-invasive test to find evidence of enterocyte cell death in infants with gastrointestinal symptoms suspicious of NEC, in order to differentiate NEC from other neonatal diseases that present with abdominal signs. Intestinal fatty acid binding protein (I-FABP) has been reported to be a useful plasma marker for early enterocyte cell death.5,6 The small (14–15 kDa) cytosolic I-FABP is specifically present in mature enterocytes of small and large intestine and is released as soon as cell membrane integrity is compromised. I-FABP is present in very small amounts in the plasma of healthy individuals, probably representing the normal turnover of enterocytes, but levels …

A pilot study on the noninvasive evaluation of intestinal damage in celiac disease using I-FABP and L-FABP.

Background and Goals In the clinical management of celiac disease, new noninvasive tools for evaluation of intestinal damage are needed for diagnosis and for follow-up of diet effects. Fatty acid binding proteins (FABP) are potentially useful for this purpose as these are small cytosolic proteins present in enterocytes and sensitive markers for intestinal mucosal damage. First, the distribution and microscopic localization of FABP in the healthy human intestine was examined. Second, levels of circulating FABP were measured in patients with celiac disease before and after introducing a gluten-free diet (GFD) and in healthy controls. Study The distribution and microscopic localization of FABP in normal human intestinal tissue was assessed using surgical intestinal specimens of 39 patients. Circulating levels of intestinal (I)-FABP and liver (L)-FABP were determined in 26 healthy volunteers and 13 patients with biopsy proven celiac disease. Ten of these patients were reevaluated within 1 year after starting GFD. Results I-FABP and L-FABP are predominantly present in the small intestine, mainly the jejunum. Moreover, FABP are expressed in cells on the upper part of the villi, the initial site of destruction in celiac disease. Circulating levels of FABP are significantly elevated in untreated patients with biopsy proven celiac disease compared with healthy controls (I-FABP: 784.7 pg/mL vs. 172.7 pg/mL, P<0.001; L-FABP: 48.4 ng/mL vs. 10.4 ng/mL, P<0.001). In response to GFD, these concentrations normalize. Conclusions Results of this pilot study strongly suggest that FABP can be used as a noninvasive method for assessment of intestinal damage in celiac disease. Besides an additional role in the diagnosis of celiac disease, FABP potentially enable noninvasive monitoring of the GFD effects.

Intestinal cytoskeleton degradation precedes tight junction loss following hemorrhagic shock.

Hemorrhagic shock (HS) leads to intestinal barrier loss, causing systemic inflammation, which in turn can ultimately lead to multiorgan dysfunction syndrome. Barrier function is based on tight junctions (TJs) between intact epithelial cells. These TJs are anchored in the cell via the filamentous actin (F-actin) cytoskeleton. We hypothesize that HS causes hypoperfusion, leading to loss of F-actin, via activation of actin-depolymerizing factor/cofilin (AC), and consequently TJ loss. This study is aimed at unraveling the changes in cytoskeleton and TJ integrity after HS in organs commonly affected in multiorgan dysfunction syndrome (liver, kidney, and intestine) and to elucidate the events preceding cytoskeleton loss. Adult rats were subjected to a nonlethal HS and sacrificed, along with unshocked controls, at 15, 30, 60, and 90 min after induction of shock. Cytoskeleton, TJ integrity loss, and its consequences were studied by assessment of globular actin, F-actin, AC, zonula occludens protein 1, claudin 3, and bacterial translocation. In the liver and kidney, TJ and the F-actin cytoskeleton remained intact at all time points studied. However, in the intestine, significant loss of F-actin and increase of globular actin was seen from 15 min after shock. This change preceded statistically significant loss of the TJ proteins claudin 3 and zonula occludens protein 1, which were observed starting at 60 min after induction of shock (P < 0.05 vs. controls). Early after induction of shock (15 and 30 min) the nonactive AC (phosphorylated AC) in the intestine was significantly decreased (by 21% and 27%, P < 0.05 vs. control), whereas total AC remained constant, reflecting an increase in activated AC in the intestine from 15 min after shock. Bacterial translocation to mesenteric lymph nodes, liver, and spleen was present from 30 min after shock. This study shows for the first time that HS results in AC activation, selective intestinal actin cytoskeleton disruption, and TJ loss very early after the onset of shock. Loss of this intestinal barrier results in translocation of toxins and bacteria, which enhances inflammation and leads to infections.ABBREVIATIONS-AC-actin-depolymerizing factor/cofilin; bpm-beats per minute; F-actin-filamentous actin; G-actin-globular actin; HR-heart rate; HS-hemorrhagic shock; LC-myosin light chain; MODS-multiorgan dysfunction syndrome; pAC-phosphorylated AC; tAC-total AC; TJ-tight junction; ZO-1-zonula occludens protein 1