Gaël Piton

Acute intestinal failure in critically ill patients: is plasma citrulline the right marker?

IntroductionSmall bowel functions are more complex than colon functions, and short bowel conditions are associated with increased mortality. Gastrointestinal dysfunction in critically ill patients is common, probably underestimated, and associated with a poor prognosis. However, a validated definition of acute intestinal failure is lacking, in absence of a marker to measure it. Consequently, small bowel dysfunction is not clearly integrated into the overall approach used to treat ICU patients.Materials and MethodsReview of the literature on gastrointestinal dysfunction in critically ill patients, and proposition of a definition of acute intestinal failure.Conclusion On the one hand, small bowel ischemia is related to acute reduction of enterocyte mass and loss of gut barrier function by epithelial lifting of villi. On the other hand, systemic inflammatory response syndrome (SIRS) and sepsis could be linked to an acute dysfunction of enterocytes without enterocyte reduction. Citrulline is an amino acid mainly synthesized by small bowel enterocytes. Various contexts of chronic and acute reduction of enterocyte mass have been correlated with low plasma citrulline concentration. Critically ill patients with shock have an acute reduction of enterocyte mass and reduced gut citrulline synthesis, leading to a low plasma citrulline concentration. Acute intestinal failure could be defined as an acute reduction of enterocyte mass and/or acute dysfunction of enterocytes, associated or not with loss of gut barrier function. The influence of SIRS and acute renal failure on plasma citrulline concentration and the value of this concentration as an indicator of acute intestinal failure in critically ill patients must be further evaluated.

Enterocyte damage in critically ill patients is associated with shock condition and 28-day mortality.

Objectives:Small bowel dysfunction in critically ill patients is frequent, underdiagnosed, and associated with poor prognosis. Intestinal fatty acid-binding protein is a marker of enterocyte damage, and plasma citrulline concentration is a marker of functional enterocyte mass. Primary objective was to identify factors associated with intestinal fatty acid-binding protein in critically ill patients. Secondary objectives were to study factors associated with plasma citrulline concentration and its correlation with intestinal fatty acid-binding protein. Design:Prospective observational study. Setting:ICU in a University Hospital Patients:Critically ill patients 18 years old or older with an expected length of ICU stay 48 hours or more, without pregnancy, chronic small bowel disease, or chronic renal failure. Interventions:None. Measurements and Main Results:Plasma intestinal fatty acid-binding protein and citrulline concentrations, and variables relating to prognosis and treatment, were measured at admission to the ICU. One hundred and three patients were included. Intestinal fatty acid-binding protein elevation at admission to the ICU was associated with catecholamine support, higher lactate concentration, higher Sequential Organ Failure Assessment score, and higher international normalized ratio (all p ⩽ 0.001). Plasma citrulline concentration less than or equal to 10 &mgr;mol/L at admission to the ICU was associated with higher intra-abdominal pressure, higher plasma C reactive protein concentration, and more frequent antibiotic use (all p ⩽ 0.005). There was no correlation between plasma levels of intestinal fatty acid-binding protein and citrulline. At ICU admission, Sequential Organ Failure Assessment score ≥12, plasma citrulline ⩽ 12.2 &mgr;mol/L, and plasma intestinal fatty acid-binding protein concentration ≥355 pg/mL were all independently associated with 28-day mortality (odds ratio, 4.39 [1.48–13.03]; odds ratio, 5.17 [1.59–16.86]; and odds ratio, 4.46 [1.35–14.74], respectively). Conclusions:In critically ill patients, enterocyte damage is frequent, and it is significantly associated with shock and 28-day mortality. The link between intestinal fatty acid-binding protein and plasma citrulline concentrations in critically ill patients needs to be further evaluated.

Infliximab treatment for steroid-refractory acute graft-versus-host disease after orthotopic liver transplantation: a case report.

Acute graft‐versus‐host disease (GVHD) following orthotopic liver transplantation is a rare but severe disease with a 75% death rate in adults. Various therapeutic strategies have been proposed for steroid‐refractory GVHD, but there is still no consensus. Tumor necrosis factor‐alpha is a key inflammatory cytokine involved in acute GVHD physiopathology, and infliximab has shown encouraging results for the treatment of acute GVHD following hematopoietic stem cell transplantation. We report the first case of acute GVHD following liver transplantation that was refractory to steroids and anti‐lymphocyte globulin but was successfully treated with infliximab. Liver Transpl 15:682–685, 2009.

Biomarkers of gut barrier failure in the ICU.

PURPOSE OF REVIEW Gut barrier failure is associated with bacterial translocation, systemic inflammation, and is presumed to be associated with the development of multiple organ dysfunction syndrome. As the gut barrier function is carried out by a monolayer of enterocytes, a minimum requirement is the integrity of the enterocytes, and controlled paracellular permeability between adjacent enterocytes. Many factors can cause critically ill patients to lose gut barrier function by a mechanism of enterocyte damage; for example, small bowel ischemia or hypoxia, sepsis, systemic inflammatory response syndrome, or absence of enteral feeding. RECENT FINDINGS Two enterocyte biomarkers may help the intensivist to identify enterocyte damage and dysfunction, namely plasma citrulline, a biomarker of functional enterocyte mass, and plasma or urinary intestinal fatty acid-binding protein, a marker of enterocyte damage. This review focuses on results obtained with these biomarkers in the context of critical care, in particular: prevalence of enterocyte biomarker abnormalities; mechanisms associated with enterocyte damage and dysfunction; link with systemic inflammation, bacterial translocation, and clinical intestinal dysfunction; prognostic value of enterocyte biomarkers. Lastly, we also review the limits of these biomarkers. SUMMARY Enterocyte biomarkers may help the intensivist to identify patients presenting with intestinal damage, and who are at risk of bacterial translocation and systemic inflammatory response syndrome, as well as those with decreased enterocyte function, at risk of malabsorption. Enterocyte biomarkers should be interpreted with caution in the critically ill and should be interpreted within the overall clinical context of the patient.

Small Bowel Adenocarcinomas Complicating Crohn's Disease Are Associated With Dysplasia: A Pathological and Molecular Study.

Background:Crohns disease (CD) is associated with an increased risk of small bowel adenocarcinoma (SBA). However, there are no guidelines for the screening and early diagnosis of SBA. Colorectal cancer associated with chronic colitis arises from dysplasia. High-risk patients benefit from surveillance colonoscopies aimed to detect dysplasia. The dysplasia–carcinoma sequence remains poorly documented in CD-associated SBA. Moreover, molecular data about SBA complicating CD and associated dysplasia are very limited. We therefore assessed dysplasia and several key molecular markers of carcinogenesis in SBA and dysplasia developed in patients with CD. Methods:Forty-five SBA complicating CD and 4 specimens with dysplasia without SBA were screened. In SBA, we looked for dysplasia and determined their pathological characteristics (type, grade, distribution). We also stained for mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), p53, &bgr;-catenin, and p16 and looked for KRAS, BRAF and PIK3CA mutations. Results:All neoplastic lesions, except 1 lesion, were found in inflamed mucosal areas. Dysplasia was found in 20 of 41 patients with SBA (49%). Dysplasia was flat or raised, low grade or high grade, and adjacent or distant to concomitant SBA. Molecular markers of SBA carcinogenesis complicating CD were similar to those observed in chronic colitis-related colorectal cancer (KRAS, BRAF, p53, MSI), although differences were observed for &bgr;-catenin and p16. No PIK3CA mutations were observed. Conclusions:These results suggest that there is an inflammation–dysplasia–adenocarcinoma sequence in at least half of CD-related SBA, similar to what is observed in chronic colitis-related colorectal cancer and may have implications for the prevention and treatment of this cancer.

Catecholamine use is associated with enterocyte damage in critically ill patients.

ABSTRACT Small bowel damage is frequent but underdiagnosed among critically ill patients with shock. High catecholamine doses may have a deleterious effect on mesenteric blood flow. Plasma intestinal fatty acid–binding protein (I-FABP) concentration is a marker of enterocyte damage, whereas plasma citrulline concentration is a marker of functional enterocyte mass. We hypothesized that high doses of catecholamines in critically ill patients may be associated with enterocyte damage. This study aimed to determine the link between catecholamine use and dose with enterocyte damage. This is a prospective observational study performed in a large regional university teaching hospital. Critically ill patients requiring epinephrine and/or norepinephrine at admission to a medical intensive care unit (ICU) were included, as well as controls not receiving catecholamines. We evaluated at admission plasma I-FABP and citrulline concentrations, abdominal perfusion pressure (APP), and variables relating to prognosis and treatment. Patients were categorized according to the quartiles of catecholamine dose at ICU admission. Sixty critically ill patients receiving catecholamines and 27 not receiving catecholamines were included. Plasma I-FABP was higher among patients receiving catecholamine than in controls. Among patients receiving catecholamines, a dose of 0.48 &ggr; kg−1 min−1 or more at ICU admission was associated with a higher I-FABP concentration. A Sepsis-related Organ Failure Assessment score higher than 11 and plasma I-FABP more than 524 pg mL−1 at ICU admission were independently associated with 28-day mortality (odds ratio, 4.0 [1.24–12.95] and odds ratio, 4.90 [1.44–16.6], respectively). Catecholamine use is associated with I-FABP elevation in critically ill patients. Critically ill patients receiving more than 0.48 &ggr; kg−1 min−1 of epinephrine and/or norepinephrine at ICU admission have high I-FABP concentrations. This suggests that enterocyte damage reflects the severity of shock, and an adverse effect of catecholamines per se is possible.

Acute Ischemic Pancreatitis Following Cardiac Arrest: A Case Report

CONTEXT Ischemia is an established cause of acute pancreatitis; however, acute pancreatitis has never been reported after cardiac arrest. CASE REPORT We report a case of acute pancreatitis following cardiac arrest with prolonged cardiopulmonary resuscitation in a 58-year-old man, the mechanism of which is likely to be ischemic. The patient developed severe ischemic encephalopathy, leading to death. Possible causes of acute pancreatitis in a context of cardiopulmonary resuscitation are discussed. CONCLUSION In case of abdominal distension following cardiac arrest, diagnoses of mesenteric ischemia and acute ischemic pancreatitis should be considered. Such digestive complications occurring after cardiac arrest probably reflect the severity of the ischemia.

Acute Mesenteric Ischemia Among Postcardiac Surgery Patients Presenting with Multiple Organ Failure

Background: Acute mesenteric ischemia (AMI) is a rare but severe complication after cardiac surgery. However, AMI is likely to be more frequent in the subgroup of patients presenting with multiple organ failure after a cardiac surgery. The primary objective of this study was to identify AMI risk factors among patients requiring intensive care unit (ICU) admission after cardiac surgery. Methods: Retrospective observational study of all the patients requiring admission to two ICUs in a large university hospital after a cardiac surgery procedure. AMI confirmation was based on abdominal computed tomography scan, digestive endoscopy, laparotomy, or postmortem examination. Univariate and multivariate analyses were done to compare pre- and in-ICU characteristics between patients with or without AMI. Results: Between 2007 and 2013, a cardiac surgery was performed in 4,948 patients, of whom 320 patients (6%) required ICU admission for multiple organ failure. AMI was confirmed in 10% of the patients admitted to the ICU for multiple organ failure (33/320). The prognosis of these patients was extremely poor with 28- and 90-day mortality rates of 64% and 83%, respectively. Nonocclusive mesenteric ischemia (NOMI) was the main mechanism involved in 83% of the patients. Coronary artery bypass graft, need for blood transfusion during cardiopulmonary bypass, aspartate aminotransferase at least 100 UI/L, and Simplified Acute Physiology Score II at least 50 at ICU admission were independently associated with AMI. An AMI risk score based upon these four risk factors was able to identify three classes of risk: low risk (<1%), intermediate risk (9%), and high risk (29%). Conclusion: AMI is a frequent condition among patients presenting with multiple organ failure after cardiac surgery, occurring in 10% of them. The prognosis of AMI is extremely poor. The main mechanism of AMI is NOMI, occurring in approximately 80% of patients. Further progress should be performed on prevention and earlier diagnosis.

Enterocyte Damage: A Piece in the Puzzle of Post-Cardiac Arrest Syndrome.

ABSTRACT Cardiac arrest is considered to be a cause of small bowel ischemia, but the consequences of cardiac arrest on the human small bowel have been rarely studied. Plasma citrulline concentration is a marker of functional enterocyte mass, and plasma intestinal fatty acid–binding protein (I-FABP) concentration is a marker of enterocyte damage. We aimed to measure enterocyte biomarkers after cardiac arrest and to study the prognostic value of biomarker abnormalities. This is a prospective, observational, single-center study of patients admitted to the intensive care unit (ICU) for cardiac arrest, evaluating plasma citrulline and I-FABP concentrations at admission and after 24 h and variables according to the Utstein criteria. Variables according to 28-day Cerebral Performance Category score of 1 to 2 (good neurological outcome) versus 3 to 5 (poor neurological outcome) were compared. Sixty-nine patients with cardiac arrest of both cardiac and hypoxic origin were included. At ICU admission, plasma citrulline concentration was low in 65% and plasma I-FABP was elevated in 82% of the patients. After 24 h, plasma citrulline was low in 82% and I-FABP was normal in 60% of the patients. Patients with a poor neurological outcome had a lower plasma citrulline concentration and a higher I-FABP concentration at ICU admission. By multivariate analysis, plasma citrulline levels of 13.1 &mgr;mol L−1 or less and I-FABP more than 260 pg mL−1 were independently associated with a poor neurological outcome (odds ratio, 21.9 [2.2–215], and odds ratio, 13.6 [1.4–129], respectively). Cardiac arrest resuscitation is associated with evidence of small bowel mucosal damage in most patients, with a short and intense I-FABP elevation at admission and a decrease in citrulline concentration during the first day. In this study, low plasma citrulline and high I-FABP concentrations at ICU admission were predictive of a poor neurological outcome. This study confirms that cardiac arrest is a model of small bowel mucosal ischemia and suggests that enterocyte damage is a piece in the puzzle of post–cardiac arrest syndrome.

Thrombotic thrombocytopenic purpura associated with severe acute pancreatitis in a context of decreased ADAMTS13 activity: a case report.

Thrombotic thrombocytopenic purpura (TTP) is a severe multisystemic microvascular disease defined by the association of hemolytic anemia, thrombocytopenia, acute renal failure, fever, and neurological disorders. The pathophysiology has recently been elucidated by the discovery of a von Willebrand factor-cleaving protease (ADAMTS13) deficiency involved in platelet aggregation and ischemia. The association between TTP and acute pancreatitis (AP) has rarely been reported, described either as a cause or a consequence. The role of ADAMTS13 during AP is still unknown. We describe the case of a 41-year-old woman who developed a TTP, with decreased ADAMTS13 activity, associated with severe AP. Published cases of thrombotic microangiopathy associated with AP are reviewed. The pathophysiology, management, prognostic factors, and rationale for treatment are discussed. AP should be sought in patients with TTP presenting with abdominal pain. On the other hand, TTP should be considered in patients with AP and thrombocytopenia.