Clinical paperMarkers of intestinal injury are associated with endotoxemia in successfully resuscitated patients☆
Introduction
Sudden cardiac death is a major public health issue leading to an estimate of 300,000 deaths each year in United States.1 Despite advances in resuscitation of cardiac arrest patients, considerable mortality occurs due to post-resuscitation shock (PRS).2 The pathophysiology of PRS is complex and multifactorial.3, 4 Besides myocardial failure, the whole-body ischemia–reperfusion syndrome induces a sepsis-like syndrome with an impairment of vasoregulation and oxygen delivery. This phenomenon has been related to a systemic inflammation characterized by the release of pro-inflammatory cytokines like TNF-α and IL-6.5 The mechanisms that lead to this pro-inflammatory response include an endothelial dysfunction induced by an oxygen debt, the subsequent alteration of the coagulation pathway6 and the production of reactive oxygen species during the reperfusion phase. The cytokines released after cardiac arrest are associated with a systemic endotoxemia.5 As endotoxin is the main activator of the Toll-Like Receptor 4 (TLR4)/Nuclear Factor-kappa B pathway one can hypothesize that endotoxin may be the trigger of pro-inflammatory cytokines release.7
Cardiac arrest is a prototypic situation where a transient and global splanchnic anoxic–ischemia occurs. We hypothesized that the subsequent ischemia–reperfusion could lead to acute intestinal injury that would increase intestinal permeability and thus, favor endotoxin translocation from the gut flora. Post-resuscitation intestinal injury has been suggested from endoscopic and post-mortem observations of mesenteric ischemia or necrosis following successfully resuscitated cardiac arrest.8, 9, 10 Beside endoscopy and autopsy, small bowel status can be mainly estimated with 2 biomarkers, plasma citrulline concentration and urinary intestinal fatty-acid binding protein (IFABP). Citrulline is an amino acid involved in intermediary metabolism that is not incorporated to proteins. Circulating citrulline is mainly produced by enterocytes of the small bowel and has been well correlated with the functional enterocyte mass in several studies of chronically ill patients such as short bowel syndrome, chemotherapy, radiotherapy or after short bowel transplantation (for review see Ref. [11]) and also recently with prognosis in ICU patients.12, 13 The IFABP is an enterocyte protein located at the luminal pole of the cells and is therefore normally absent of systemic circulation. IFABP is released in case of intestinal permeability and has been shown to be a good marker of intestinal ischemia14 and to be associated with higher severity in different critical diseases such as acute pancreatitis15 or meningococcemia.16
Considering that post-cardiac arrest patients are at high risk of gut injury, our main objectives were: (i) to search possible gut damages using biomarkers (IFABP and citrulline); (ii) to determine the incidence and amount of endotoxemia; (iii) to search for a correlation between gut injury biomarkers and endotoxemia.
Section snippets
Study setting and patients
The study was conducted from November 2009 to March 2010 in the tertiary ICU of Cochin university hospital specialized in the management of post OHCA patients recruited from a large urban area (Paris, France). Following resuscitation after cardiac arrest, adult patients admitted in this ICU were prospectively included once written information had been delivered to relatives. Exclusion criteria were presence of prodrome more than 60 min before collapse, chronic terminal renal failure, chronic gut
Results
Main characteristics of the 21 studied patients are summarized in Table 1. Etiology of OHCA was cardiac in 14 patients, hypoxic in 5 patients and a pulmonary embolism in 2 patients. Median time between cardiac arrest and basic life support (“no flow”) and median time between basic life support and ROSC (“low flow”) were short (2 and 10 min respectively). Post-resuscitation shock was common (62%) and mortality rate in ICU was high (62%). All our patients except one, which died before hypothermia
Discussion
The main findings of this pilot study are: (i) markers of gut injury are almost constantly elevated after resuscitated cardiac arrest, (ii) high level of endotoxemia is frequent in this setting and (iii) endotoxemia is correlated with the severity of gut injury and seems to be associated with shock and organ failure.
To the best of our knowledge, our research is the first to study the biomarkers citrulline and IFABP after cardiac arrest in human. We observed initial abnormalities of these
Author's contributions
DG, JPM, LC and AC drafted the manuscript. DG, EG, JF, FP, JSM enrolled patients. NN measured plasma citrulline, DG and EG measured IFABP and endotoxin. All authors read and approved the final manuscript. This study was presented in abstract form at the 23rd EISCM congress in Barcelona, 2010.
Conflicts of interest statement
None of the authors have any financial interests or affiliations with commercial organizations whose products or services are related to the subject matter of this manuscript (i.e., no existing conflicts of interest). Financial support was provided solely from departmental resources. Spectral Diagnostics donated endotoxin kits without any access to data management. The company had no role in the study design, manuscript writing or decision to submit the manuscript for publication.
Acknowledgments
We thank Dr N. Marin for help in sample collection, C. Rousseau for technical advices and N. Kentish-Barnes for critical reading of the manuscript.
References (38)
- et al.
Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. a scientific statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke
Resuscitation
(2008) - et al.
Coagulopathy after successful cardiopulmonary resuscitation following cardiac arrest: implication of the protein C anticoagulant pathway
J Am Coll Cardiol
(2005) - et al.
TLR signaling
Semin Immunol
(2007) - et al.
Gut dysfunction and endoscopic lesions after out-of-hospital cardiac arrest
Resuscitation
(2005) - et al.
Citrulline as a biomarker of intestinal failure due to enterocyte mass reduction
Clin Nutr
(2008) - et al.
Cardiac arrest and cardiopulmonary resuscitation outcome reports: update and simplification of the Utstein templates for resuscitation registries. A statement for healthcare professionals from a task force of the international liaison committee on resuscitation (American Heart Association, European Resuscitation Council, Australian Resuscitation Council, New Zealand Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Southern Africa)
Resuscitation
(2004) - et al.
A rapid assay of endotoxin in whole blood using autologous neutrophil dependent chemiluminescence
J Immunol Methods
(1998) - et al.
The 2009 ESPEN Sir David Cuthbertson. Citrulline: a new major signaling molecule or just another player in the pharmaconutrition game?
Clin Nutr
(2010) - et al.
Intestinal ischaemia during cardiac arrest and resuscitation: comparative analysis of extracellular metabolites by microdialysis
Resuscitation
(2003) - et al.
A new model to study intestinal ischemia–reperfusion damage in man
J Surg Res
(2011)
Human intestinal ischemia–reperfusion-induced inflammation characterized: experiences from a new translational model
Am J Pathol
Intestinal endotoxemia. Clinical significance
Gastroenterology
Endotoxemia contributes to the immune paralysis in patients with cirrhosis
J Hepatol
Hypothermia and anesthetic postconditioning influence the expression and activity of small intestinal proteins possibly involved in ischemia/reperfusion-mediated events following cardiopulmonary resuscitation
Resuscitation
ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society
Circulation
Is hypothermia after cardiac arrest effective in both shockable and nonshockable patients?: insights from a large registry
Circulation
Postcardiac arrest syndrome: from immediate resuscitation to long-term outcome
Ann Intensive Care
Successful cardiopulmonary resuscitation after cardiac arrest as a “sepsis-like” syndrome
Circulation
Unexpected findings and complications at autopsy after cardiopulmonary resuscitation (CPR)
Arch Intern Med
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A Spanish translated version of the abstract of this article appears as Appendix in the final online version at http://dx.doi.org/10.1016/j.resuscitation.2012.06.010.