Early diagnosis and follow-up of intestinal damage in clinical medicine
Evaluation of intestinal pathology in patients of all age groups has long been a challenge for clinicians. Numerous patients present with abdominal complaints, which are frequently aspecific and therefore correspond to pathologies of most intra- and even to some extra-abdominal organs. Laboratory tests and imaging techniques are often helpful in revealing disorders of organs, including the liver, pancreas, heart, and kidneys. However, it is still difficult to diagnose intestinal pathology in patients presenting with abdominal complaints. The current standard technique for assessing intestinal status is endoscopy with biopsy. For some diseases this is helpful; however, it is invasive, associated with morbidity, sometimes requires sedation, expensive, and only assesses the function of the biopsied fraction. Moreover, for neutropenic and/or thrombocytopenic patients, the procedure is physically hazardous and often ethically unacceptable. Therefore, a major delay in diagnosis occurs in patients with e.g. NEC, chemotherapy-induced mucositis, acute mesenteric ischaemia, and celiac disease[37,38]. Such a diagnostic delay results in delayed treatment, which is accompanied by higher morbidity and mortality rates. In line with these diagnostic concerns, the follow-up of numerous intestinal diseases is hampered by the absence of rapid, non-invasive diagnostic means to assess intestinal damage for evaluation of the effects of treatment on the recovery of the disorder.
Potential involvement of the gut in the development of postoperative or posttraumatic complications
Patients undergoing major surgery or sustaining severe trauma are at risk of developing morbidity and mortality from post-operative or post-traumatic systemic inflammatory response syndrome (SIRS), sepsis, and multiple organ failure (MOF). Development of such potentially lethal complications in relatively healthy surgical or trauma patients is poorly understood. Experimental animal studies have generated the hypothesis that the intestines are central in the origin of post-operative and post-traumatic sequelae[39-41]. Human studies have contributed insufficiently to gain insight in the applicability of this hypothesis. Recognition of patients at risk of developing post-operative or post-traumatic SIRS, sepsis, and MOF is important, as patients with these clinical syndromes have the highest noncardiac mortality rate of patients in the intensive care unit (ICU)[39-42].
Experimental animal models, resembling the clinical situation of major surgery and trauma, show that haemorrhagic shock leads to disruption of the gut wall integrity, measured by derangement of tight-junctions and elevated circulating levels of FABP, originating from damaged intestinal epithelial cells[43,44]. Moreover, leakage of macromolecules, microbial products, and microbiota from the intestinal lumen into the circulation and mesenteric lymph nodes, spleen, and liver occurs. The inflammatory response to microbial products, such as endotoxins, has been reported to be provoked via various rapidly induced innate immune mechanisms, ranging from Toll Like Receptors to complement activation. Supportive of the importance of the gut in the development of postoperative complications is the observation that protection of the gut wall integrity in hemorrhagically shocked animals by administration of probiotic strains, which inhibit the adhesion of enteric pathogens to intestinal epithelial cells, can result in abrogation of both local and systemic inflammatory responses. However, administration of probiotic strains might also have unwanted side-effects, including disruption of intestinal tight junctions and increase of bacterial translocation.
Studies in patients undergoing major gastrointestinal, cardiac, or vascular surgery, investigating the role of the gut in the development of post-operative complications, are largely restricted to data on increased intestinal permeability for sugars, 51Cr-ethylenediaminetetraacetic acid (51Cr-EDTA), and the circulatory levels of endotoxin[14,47-49]. Increased intestinal absorption of sugars or 51Cr-EDTA, indirect measures for gut barrier loss, in patients following major surgery support data obtained from animal studies, indicating that the gut barrier is injured after major surgery[14,48-50]. However, other reports show no changes in intestinal permeability. Moreover, the value of measuring gut integrity with sugar probes is debatable[8,9]. Similar results are reported on the development of endotoxemia. Several authors report on increased circulating levels of endotoxin or reduced values of anti-endotoxin antibody during major surgery, suggesting leakage of gut derived bacterial products from the gut lumen into the circulation due to an impaired epithelial barrier, whereas others show unaltered endotoxin concentrations[49,52]. Data showing better survival in patients with pre-operatively higher anti-endotoxin titres support the theory of intestinal contribution in the development of postoperative complications. In conclusion, the debate regarding involvement of the gut in patients undergoing major surgery is still ongoing.
Three recent studies show the temporary presence of intestinal villous cell damage, measured by increased urinary levels of I-FABP, in patients undergoing cardio-vascular surgery with cardiopulmonary bypass (CPB)[54-56]. Patients with high urinary I-FABP levels developed postoperative gastro-intestinal complications. The use of CPB was shown to be responsible for alterations in blood flow with consequent intestinal mucosal hypoxia and villous tip ischaemia[55,56]. Furthermore, intestinal injury correlated positively with markers of systemic inflammation. We recently reported, in patients undergoing major non-abdominal surgery, a similar influence of reduction in blood pressure on the provocation of intestinal villous cell injury, without the use of extracorporeal circulation. A significant inverse association between mean arterial pressure and succeeding plasma levels of I-FABP and I-BABP was found, which indicates that systemic hypotension is correlated with intestinal mucosal cell injury. Anaesthetics, leading to decreased systemic vascular resistance, mainly cause systemic hypotension. Finally, splanchnic hypoperfusion (measured by gastric mucosal PiCO2 and Pr-aCO2-gap) correlated strongly with intestinal mucosal damage (assessed by plasma I-FABP) at all observed time-points during surgery.
In conclusion, the results of these studies show, for the first time, the relation between altered splanchnic perfusion and the development of intestinal mucosal cellular damage in patients undergoing major surgery. Collectively, these findings shed new light on the potential role of intestinal barrier compromise during major surgery, which was deduced from numerous animal studies, but has now been reported, for the first time, in relatively healthy children and adolescents undergoing major (non-abdominal) surgery. Furthermore, these results indicate a need to re-examine currently accepted criteria of haemodynamic parameters, both regarding the use of extra-corporeal circulation and accepted systemic hypotension, in patients undergoing major surgery.
The presence of intestinal damage does not show any cause-and-effect relationship with the development of sepsis or MOF. Moreover, intestinal damage may be part of more generalised tissue damage with epithelial barrier dysfunction in lung, liver, and kidney. These studies are, however, the basis for further research to clarify the onset of intestinal damage. In addition, assessment of intestinal epithelial damage in patients with sepsis or undergoing major surgery might have important clinical implications. Evaluation of intestinal epithelial cell damage as a consequence of splanchnic hypoperfusion, could help to monitor preoperative treatment or therapy in patients with shock directed at restoration of peripheral perfusion and prevention of organ damage.