Endothelial Dysfunction as a Component of Severe Acute Respiratory Syndrome Coronavirus 2-Related Multisystem Inflammatory Syndrome in Children With Shock.

TRIAL REGISTRATION: NCT04420468. OBJECTIVES: Severe acute respiratory syndrome coronavirus 2-related multisystem inflammatory syndrome in children is frequently associated with shock; endothelial involvement may be one of the underlying mechanisms. We sought to describe endothelial dysfunction during multisystem inflammatory syndrome in children with shock and then assess the relationship between the degree of endothelial involvement and the severity of shock. DESIGN: Observational study. SETTING: A PICU in a tertiary hospital. PATIENTS: Patients aged under 18 (n = 28) with severe acute respiratory syndrome coronavirus 2-related multisystem inflammatory syndrome in children and shock, according to the Centers for Disease Control and Prevention criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Correlations between endothelial marker levels and shock severity were assessed using Spearman coefficient. The median (interquartile range) age was 9 years (7.5-11.2 yr). Sixteen children presented with cardiogenic and distributive shock, 10 presented with cardiogenic shock only, and two presented with distributive shock only. The median left ventricular ejection fraction, troponin level, and lactate level were, respectively, 40% (35-45%), 261 ng/mL (131-390 ng/mL), and 3.2 mmol/L (2-4.2 mmol/L). Twenty-five children received inotropes and/or vasopressors; the median Vasoactive and Inotropic Score was 8 (5-28). Plasma levels of angiopoietin-2 (6,426 pg/mL [2,814-11,836 pg/mL]), sE-selectin (130,405 pg/mL [92,987-192,499 pg/mL]), von Willebrand factor antigen (344% [288-378%]), and the angiopoietin-2/angiopoietin-1 ratio (1.111 [0.472-1.524]) were elevated and significantly correlated with the Vasoactive and Inotropic Score (r = 0.45, p = 0.016; r = 0.53, p = 0.04; r = 0.46, p = 0.013; and r = 0.46, p = 0.012, respectively). CONCLUSIONS: Endothelial dysfunction is associated with severe acute respiratory syndrome coronavirus 2-related multisystem inflammatory syndrome in children with shock and may constitute one of the underlying mechanisms.

Rapid Response System Should Be Enhanced at Non-general Ward Locations: a Retrospective Multicenter Cohort Study in Korea.

BACKGROUND: A rapid response system (RRS) contributes to the safety of hospitalized patients. Clinical deterioration may occur in the general ward (GW) or in non-GW locations such as radiology or dialysis units. However, there are few studies regarding RRS activation in non-GW locations. This study aimed to compare the clinical characteristics and outcomes of patients with RRS activation in non-GW locations and in the GW. METHODS: From January 2016 to December 2017, all patients requiring RRS activation in nine South Korean hospitals were retrospectively enrolled and classified according to RRS activation location: GW vs non-GW RRS activations. RESULTS: In total, 12,793 patients were enrolled; 222 (1.7%) were non-GW RRS activations. There were more instances of shock (11.6% vs. 18.5%) and cardiac arrest (2.7% vs. 22.5%) in non-GW RRS activation patients. These patients also had a lower oxygen saturation (92.6% ± 8.6% vs. 88.7% ± 14.3%, P < 0.001) and a higher National Early Warning Score 2 (7.5 ± 3.4 vs. 8.9 ± 3.8, P < 0.001) than GW RRS activation patients. Although non-GW RRS activation patients received more intubation (odds ratio [OR], 3.135; P < 0.001), advanced cardiovascular life support (OR, 3.912; P < 0.001), and intensive care unit transfer (OR, 2.502; P < 0.001), their hospital mortality (hazard ratio, 0.630; P = 0.013) was lower than GW RRS activation patients upon multivariate analysis. CONCLUSION: Considering that there were more critically ill but recoverable cases in non-GW locations, active RRS involvement should be required in such locations.

Relation of Magnetic Resonance Elastography to Fontan Circulatory Failure in a Cohort of Pediatric and Adult Patients.

Elevated magnetic resonance elastography (MRE)-derived liver stiffness may be associated with worse outcomes in people with Fontan circulation. We sought to evaluate the association between liver stiffness and Fontan failure or portal hypertension. Single center cross-sectional retrospective study of people with Fontan circulation who underwent MRE between 2011 and 2020. The cohort was divided into adult (age ≥ 21 years) and pediatric (< 21 years) groups. Fontan circulatory failure (FF) was defined as any of the following: death, transplantation, ventricular assist device, heart failure symptoms requiring escalation of diuretics. Radiologic portal hypertension was defined as the presence of one or more of the following: splenomegaly, ascites, or gastrointestinal varices. 128 patients were included (average age = 22.6 ± 8.7 years) and 58 (45%) were children. Median liver stiffness was 4.3 kPa (interquartile range (IQR) 3.8-5.8) for the entire cohort. Thirty patients (23%) developed FF (16 adults, 14 children). Liver stiffness was higher in adults with FF compared to those without FF (4.9 (IQR 4.0-6.0) vs. 4.2 (IQR 3.8-4.7) kPa, p = 0.04). There was no difference in liver stiffness between pediatric patients with and without FF (4.4 (IQR 4.1-5.4) vs. 4.4 (IQR 3.8-5.0), p = 0.5). Adults with radiologic portal hypertension and adults with moderate or severe atrioventricular valve regurgitation had higher liver stiffness than adults without. MRE-derived liver stiffness is associated with atrioventricular valve regurgitation, portal hypertension, and poor clinical outcomes in adults with Fontan circulation. There was no association between liver stiffness and FF in pediatric patients. This difference may be due to the progressive nature of Fontan-associated liver disease.

Type I IFNs drive hematopoietic stem and progenitor cell collapse via impaired proliferation and increased RIPK1-dependent cell death during shock-like ehrlichial infection.

Type I interferons (IFNα/ß) regulate diverse aspects of host defense, but their impact on hematopoietic stem and progenitor cells (HSC/HSPCs) during infection remains unclear. Hematologic impairment can occur in severe infections, thus we sought to investigate the impact of type I IFNs on hematopoiesis in a tick-borne infection with a virulent ehrlichial pathogen that causes shock-like disease. During infection, IFNα/ß induced severe bone marrow (BM) loss, blunted infection-induced emergency myelopoiesis, and reduced phenotypic HSPCs and HSCs. In the absence of type I IFN signaling, BM and splenic hematopoiesis were increased, and HSCs derived from Ifnar1-deficient mice were functionally superior in competitive BM transplants. Type I IFNs impaired hematopoiesis during infection by both limiting HSC/HSPC proliferation and increasing HSPC death. Using mixed BM chimeras we determined that type I IFNs restricted proliferation indirectly, whereas HSPC death occurred via direct IFNαR -mediated signaling. IFNαR-dependent signals resulted in reduced caspase 8 expression and activity, and reduced cleavage of RIPK1 and RIPK3, relative to Ifnar1-deficient mice. RIPK1 antagonism with Necrostatin-1s rescued HSPC and HSC numbers during infection. Early antibiotic treatment is required for mouse survival, however antibiotic-treated survivors had severely reduced HSPCs and HSCs. Combination therapy with antibiotics and Necrostatin-1s improved HSPC and HSC numbers in surviving mice, compared to antibiotic treatment alone. We reveal two mechanisms whereby type I IFNs drive hematopoietic collapse during severe infection: direct sensitization of HSPCs to undergo cell death and enhanced HSC quiescence. Our studies reveal a strategy to ameliorate the type I IFN-dependent loss of HSCs and HSPCs during infection, which may be relevant to other infections wherein type I IFNs cause hematopoietic dysfunction.

Plasma for burn shock resuscitation: is it time to go back to the future?

Patients with burn shock can be challenging to resuscitate. Burn shock produces a variety of physiologic derangements: Patients are hypovolemic from volume loss, have a increased systemic vascular resistance, and may have a depressed cardiac output depending on the extent of the thermal injury. Additionally, the burn wound produces a significant inflammatory cascade of events that contributes to the shock state. Fluid resuscitation is foundational for the initial treatment of burn shock. Typical resuscitation is with intravenous lactated Ringer's in accordance with well-established formulas based on burn wound size. In the past century, as therapies to treat thermal injuries were being developed, plasma was the fluid used for burn resuscitation; in fact, plasma was used in World War II and throughout the 1950s and 1960s. Plasma was abandoned because of infectious risks and complications. Despite huge strides in transfusion medicine and the increased safety of blood products, plasma has never been readopted for burn resuscitation. Over the past 15 years, there has been a paradigm shift in trauma resuscitation: Less crystalloid and more blood products are used; this strategy has demonstrated improved outcomes. Plasma is a physiologic fluid that stabilizes the endothelium. The endotheliopathy of trauma has been described and is mitigated by transfusion strategies with a 1:1 ratio of RBCs to plasma. Thermal injury also results in endothelial dysfunction: the endotheliopathy of burns. Plasma is likely a better resuscitation fluid for patients with significant burn wounds because of its capability to restore intravascular volume status and treat the endotheliopathy of burns.

Eicosanoids derived from cytochrome P450 pathway of arachidonic acid and inflammatory shock.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Septic shock, the most common form of vasodilatory shock, is a subset of sepsis in which circulatory and cellular/metabolic abnormalities are severe enough to increase mortality. Inflammatory shock constitutes the hallmark of sepsis, but also a final common pathway of any form of severe long-term tissue hypoperfusion. The pathogenesis of inflammatory shock seems to be due to circulating substances released by pathogens (e.g., bacterial endotoxins) and host immuno-inflammatory responses (e.g., changes in the production of histamine, bradykinin, serotonin, nitric oxide [NO], reactive nitrogen and oxygen species, and arachidonic acid [AA]-derived eicosanoids mainly through NO synthase, cyclooxygenase, and cytochrome P450 [CYP] pathways, and proinflammatory cytokine formation). Therefore, refractory hypotension to vasoconstrictors with end-organ hypoperfusion is a life threatening feature of inflammatory shock. This review summarizes the current knowledge regarding the role of eicosanoids derived from CYP pathway of AA in animal models of inflammatory shock syndromes with an emphasis on septic shock in addition to potential therapeutic strategies targeting specific CYP isoforms responsible for proinflammatory/anti-inflammatory mediator production.

Blood clotting and traumatic injury with shock mediates complement-dependent neutrophil priming for extracellular ROS, ROS-dependent organ injury and coagulopathy.

Polymorphonuclear (PMN) leucocytes participate in acute inflammatory pathologies such as acute respiratory distress syndrome (ARDS) following traumatic injury and shock, which also activates the coagulation system systemically. Trauma can prime the PMN nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex for an enhanced respiratory burst, but the relative role of various priming agents in this process remains incompletely understood. We therefore set out to identify mediators of PMN priming during coagulation and trauma-shock and determine whether PMN reactive oxygen species (ROS) generated in this manner could influence organ injury and coagulation. Initial experiments demonstrated that PMN are primed for predominantly extracellular ROS production by products of coagulation, which was abrogated by CD88/C5a receptor(C5aR) inhibition. The importance of this was highlighted further by demonstrating that known PMN priming agents result in fractionally different amounts of extracellular versus intracellular ROS release depending on the agent used. Plasma from trauma patients in haemodynamic shock (n = 10) also primed PMN for extracellular ROS in a C5a-dependent manner, which correlated with both complement alternative pathway activation and thrombin generation. Furthermore, PMN primed by preincubation with products of blood coagulation directly caused loss of endothelial barrier function in vitro that was abrogated by C5aR blockade or NADPH oxidase inhibition. Finally, we show in a murine model of trauma-shock that p47phox knock-out (KO) mice with PMN incapable of generating ROS were protected from inflammatory end-organ injury and activated protein C-mediated coagulopathy. In summary, we demonstrate that trauma-shock and coagulation primes PMN for predominantly extracellular ROS production in a C5a-dependent manner that contributes to endothelial barrier loss and organ injury, and potentially enhances traumatic coagulopathy.

Donation after brain death followed by circulatory death, a novel donation pattern, confers comparable renal allograft outcomes with donation after brain death.

BACKGROUND: Organ donation after brain death (DBD) is the standard strategy for organ transplantation; however, the concept of brain death is not universally accepted due to cultural beliefs and barriers amongst billions of people worldwide. Hence, a novel donation pattern has been established in China which outlines the concept of donation after brain death followed by circulatory death (DBCD). Differently from any current donation classification, this new concept is formulated based on combination of recognizing brain death and circulatory death. Should approval be gained for this definition and approach, DBCD will pave a novel donation option for billions of people who cannot accept DBD due to their cultural beliefs. METHODS: A multi-center, cohort study was conducted from February 2012 to December 2015. 523 kidney transplant recipients from four kidney transplant institutions were enrolled into the study, of which, 383 received kidneys from DBCD, and 140 from DBD. Graft and recipient survivals following transplantation were retrospectively analyzed. Postoperative complications including delayed graft function,, and acute rejection, were also analyzed for both groups. RESULTS: DBCD could achieve comparable graft and recipient survivals in comparison with DBD (Log-rank P = 0.32 and 0.86,respectively). One-year graft and recipient survivals were equal between DBCD and DBD groups (97.4% versus 97.9%, P = 0.10;98.4% versus 98.6%, P = 1.0, respectively). Furthermore, DBCD did not increase incidences of postoperative complications compared with DBD, including delayed graft function (19.3% versus 22.1%, P = 0.46) and acute rejection (9.1% versus 8.6%, P = 1.0). Additionally, antithymocyte globulin as induction therapy and shorter warm ischemia time decreased incidence of delayed graft function in DBCD group (16.8% on antithymocyte globulin versus 27.2% on basiliximab, P = 0.03; 16.7% on ≤18 min versus 26.7% on > 18 min group, P = 0.03). CONCLUSIONS: Kidney donation through DBCD achieves equally successful outcomes as DBD, and could provide a feasible path to graft availability for billions of people who face barriers to organ donation from DBD.

Mesenchymal stromal cell-derived extracellular vesicles attenuate lung ischemia-reperfusion injury and enhance reconditioning of donor lungs after circulatory death.

BACKGROUND: Lung ischemia-reperfusion (IR) injury after transplantation as well as acute shortage of suitable donor lungs are two critical issues impacting lung transplant patients. This study investigates the anti-inflammatory and immunomodulatory role of human mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (EVs) to attenuate lung IR injury and improve of ex-vivo lung perfusion (EVLP)-mediated rehabilitation in donation after circulatory death (DCD) lungs. METHODS: C57BL/6 wild-type (WT) mice underwent sham surgery or lung IR using an in vivo hilar-ligation model with or without MSCs or EVs. In vitro studies used primary iNKT cells and macrophages (MH-S cells) were exposed to hypoxia/reoxygenation with/without co-cultures with MSCs or EVs. Also, separate groups of WT mice underwent euthanasia and 1 h of warm ischemia and stored at 4 °C for 1 h followed by 1 h of normothermic EVLP using Steen solution or Steen solution containing MSCs or EVs. RESULTS: Lungs from MSCs or EV-treated mice had significant attenuation of lung dysfunction and injury (decreased edema, neutrophil infiltration and myeloperoxidase levels) compared to IR alone. A significant decrease in proinflammatory cytokines (IL-17, TNF-α, CXCL1 and HMGB1) and upregulation of keratinocyte growth factor, prostaglandin E2 and IL-10 occurred in the BAL fluid from MSC or EV-treated mice after IR compared to IR alone. Furthermore, MSCs or EVs significantly downregulated iNKT cell-produced IL-17 and macrophage-produced HMGB1 and TNF-α after hypoxia/reoxygenation. Finally, EVLP of DCD lungs with Steen solution including MSCs or EVs provided significantly enhanced protection versus Steen solution alone. Co-cultures of MSCs or EVs with lung endothelial cells prevents neutrophil transendothelial migration after exposure to hypoxia/reoxygenation and TNF-α/HMGB1 cytomix. CONCLUSIONS: These results suggest that MSC-derived EVs can attenuate lung inflammation and injury after IR as well as enhance EVLP-mediated reconditioning of donor lungs. The therapeutic benefits of EVs are in part mediated through anti-inflammatory promoting mechanisms via attenuation of immune cell activation as well as prevention of endothelial barrier integrity to prevent lung edema. Therefore, MSC-derived EVs offer a potential therapeutic strategy to treat post-transplant IR injury as well as rehabilitation of DCD lungs.

Adult heart transplantation with distant procurement and ex-vivo preservation of donor hearts after circulatory death: a case series.

BACKGROUND: Orthotopic heart transplantation is the gold-standard long-term treatment for medically refractive end-stage heart failure. However, suitable cardiac donors are scarce. Although donation after circulatory death has been used for kidney, liver, and lung transplantation, it is not used for heart transplantation. We report a case series of heart transplantations from donors after circulatory death. METHODS: The recipients were patients at St Vincent's Hospital, Sydney, Australia. They received Maastricht category III controlled hearts donated after circulatory death from people younger than 40 years and with a maximum warm ischaemic time of 30 min. We retrieved four hearts through initial myocardial protection with supplemented cardioplegia and transferred to an Organ Care System (Transmedics) for preservation, resuscitation, and transportation to the recipient hospital. FINDINGS: Three recipients (two men, one woman; mean age 52 years) with low transpulmonary gradients (<8 mm Hg) and without previous cardiac surgery received the transplants. Donor heart warm ischaemic times were 28 min, 25 min, and 22 min, with ex-vivo Organ Care System perfusion times of 257 min, 260 min, and 245 min. Arteriovenous lactate values at the start of perfusion were 8·3-8·1 mmol/L for patient 1, 6·79-6·48 mmol/L for patient 2, and 7·6-7·4 mmol/L for patient 3. End of perfusion lactate values were 3·6-3·6 mmol/L, 2·8-2·3 mmol/L, and 2·69-2·54 mmol/L, respectively, showing favourable lactate uptake. Two patients needed temporary mechanical support. All three recipients had normal cardiac function within a week of transplantation and are making a good recovery at 176, 91, and 77 days after transplantation. INTERPRETATION: Strict limitations on donor eligibility, optimised myocardial protection, and use of a portable ex-vivo organ perfusion platform can enable successful, distantly procured orthotopic transplantation of hearts donated after circulatory death. FUNDING: NHMRC, John T Reid Charitable Trust, EVOS Trust Fund, Harry Windsor Trust Fund.

Inferior vena cava calibre on paediatric trauma CT may be a useful predictor for the development of shock.

AIM: To investigate whether inferior vena cava (IVC) calibre on paediatric trauma computed tomography (CT) can help anticipate outcomes in children. MATERIALS AND METHODS: The imaging and clinical records of 52 paediatric trauma admissions to the level 1 major trauma centre at St George's Hospital, London, UK, were retrospectively reviewed. The IVC dimensions, evidence of significant haemorrhage on CT, and the presence of components of the classical hypoperfusion complex, such as bowel and adrenal hyperenhancement, were recorded. Clinical data included observations at the time of admission and for the subsequent 48-hour period where available, blood gas results, length of stay, and mortality. RESULTS: There was a significant relationship between IVC dimensions in this cohort and the development of shock during the 24-hour admission period. IVC dimensions did not, however, reflect the haemodynamic status at the time of admission, and were not predictive of a longer hospital stay. There were no mortalities among the cases. A weak correlation was also seen with serum lactate, a finding that has also been seen in adults, but is of uncertain clinical significance. CONCLUSIONS: IVC calibre was found to be a more useful predictor of shock than heart rate or blood pressure, and may, therefore, prove to be a useful predictor of impending haemodynamic instability in children as it is in adults. Although the study was carried out at a busy unit, the numbers are acknowledged to be small and a larger study would be needed to validate these findings and identify whether there is any variation in the CT appearances between different age groups.

Validation of the Shock Index, Modified Shock Index, and Age Shock Index for Predicting Mortality of Geriatric Trauma Patients in Emergency Departments.

The shock index (SI), modified shock index (MSI), and age multiplied by SI (Age SI) are used to assess the severity and predict the mortality of trauma patients, but their validity for geriatric patients is controversial. The purpose of this investigation was to assess predictive value of the SI, MSI, and Age SI for geriatric trauma patients. We used the Emergency Department-based Injury In-depth Surveillance (EDIIS), which has data from 20 EDs across Korea. Patients older than 65 years who had traumatic injuries from January 2008 to December 2013 were enrolled. We compared in-hospital and ED mortality of groups categorized as stable and unstable according to indexes. We also assessed their predictive power of each index by calculating the area under the each receiver operating characteristic (AUROC) curve. A total of 45,880 cases were included. The percentage of cases classified as unstable was greater among non-survivors than survivors for the SI (36.6% vs. 1.8%, P < 0.001), the MSI (38.6% vs. 2.2%, P < 0.001), and the Age SI (69.4% vs. 21.3%, P < 0.001). Non-survivors had higher median values than survivors on the SI (0.84 vs. 0.57, P < 0.001), MSI (0.79 vs. 1.14, P < 0.001), and Age SI (64.0 vs. 41.5, P < 0.001). The predictive power of the Age SI for in-hospital mortality was higher than SI (AUROC: 0.740 vs. 0.674, P < 0.001) or MSI (0.682, P < 0.001) in geriatric trauma patients.

Postmortem CT morphometry of great vessels with regard to the cause of death for investigating terminal circulatory status in forensic autopsy.

Postmortem CT (PM-CT) is useful to investigate the viscera in situ before opening the body cavities at autopsy. The present study involved a virtual morphometric analysis of thoracic and abdominal great vessels with regard to the cause of death as a possible index of terminal circulatory status in forensic autopsy cases, using PM-CT data of forensic autopsy cases within 3 days postmortem (n = 93). Perimeters and cross-sectional areas of the aorta and vena cava depended on the age and/or gender of subjects; however, when the vessel flattening index (vFI) was calculated as the ratio of the cross-sectional area (a) to the estimated circle area having the same perimeter (l), using the formula vFI = 4πa/l(2), the vFI showed distinct differences among the causes of death without significant postmortem time dependence. The index was low for each vessel in fatal bleeding, while the vFI of the abdominal aorta and inferior vena cava was low in hyperthermia (heatstroke), but higher in drowning, hypothermia (cold exposure) and sudden cardiac death. These CT findings provide quantitative data as supplementary indicators to reinforce autopsy findings for interpreting terminal circulatory status.

Observation of vertebral artery damage using angioscopy in autopsy cases.

The vertebral arteries are important blood vessels that supply the cerebral circulation in conjunction with the internal carotid arteries. In cases of subarachnoid hemorrhage, it is necessary to examine the vertebral arteries as potential sources of bleeding due to blunt trauma (head and neck) or of cerebral embolism that originated on the surface of the damaged intima as a result of hyperflexion or hyperextension. However, a considerable part of the vertebral arterial surface is surrounded by bone, resulting in challenges during examination in a routine autopsy. In this study, angioscopy was used to inspect the vertebral artery intima for damage in cases of neck injury, head injury, or neck strangulation. Intimal damage was detected in 34 out of the total 75 cases. Of the 28 cases with cervical discopathy or fracture, 61% had intimal damage. In addition, postmortem application of computed tomography angiography was performed to identify the injured vessel in a case with traumatic subarachnoid hemorrhage, and a perforated hole was detected using angioscopy, which did not introduce autopsy-related artifacts. Therefore, angioscopy may be a useful and nondestructive method to identify intimal damage in the vertebral arteries during an autopsy.

Combined mechanism of refractory shock in primary cardiac lymphoma: a rare dilemma.

Primary cardiac lymphoma is very rare, and usually manifests after the fifth decade of life. The lack of typical manifestations makes it difficult to diagnose at an early stage that can be discovered only by echocardiography. The location of the tumour often results in cardiac compromise, which prevents the delivery of potentially curative therapies. Clinical presentations may depend on flow obstruction, infiltration of adjacent tissues, tumour embolisation, and atrioventricular (AV) disturbances. We report a rare case of primary cardiac lymphoma that presented with clinical signs of shock from two distinct mechanisms. The first mechanism was intermittent complete AV block that was caused by disruption of the electrical conduction system from tumour infiltration in addition to direct mechanical compression of the atrioventricular node by the tumour. The second mechanism, subtotal RV inflow obstruction from the bulky mass contributed to compromising venous return, which played a major role of refractory shock in this case.

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 µmol/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 µmol/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.

Dichotomy between RIP1- and RIP3-mediated necroptosis in tumor necrosis factor-α-induced shock.

Tumor necrosis factor receptor (TNFR) signaling may result in survival, apoptosis or programmed necrosis. The latter is called necroptosis if the receptor-interacting protein 1 (RIP1) inhibitor necrostatin-1 (Nec-1) or genetic knockout of RIP3 prevents it. In the lethal mouse model of TNFα-mediated shock, addition of the pan-caspase inhibitor zVAD-fmk (zVAD) accelerates time to death. Here, we demonstrate that RIP3-deficient mice are protected markedly from TNFα-mediated shock in the presence and absence of caspase inhibition. We further show that the fusion protein TAT-crmA, previously demonstrated to inhibit apoptosis, also prevents necroptosis in L929, HT29 and FADD-deficient Jurkat cells. In contrast to RIP3-deficient mice, blocking necroptosis by Nec-1 or TAT-crmA did not protect from TNFα/zVAD-mediated shock, but further accelerated time to death. Even in the absence of caspase inhibition, Nec-1 application led to similar kinetics. Depletion of macrophages, natural killer (NK) cells, granulocytes or genetic deficiency for T lymphocytes did not influence this model. Because RIP3-deficient mice are known to be protected from cerulein-induced pancreatitis (CIP), we applied Nec-1 and TAT-crmA in this model and demonstrated the deterioration of pancreatic damage upon addition of these substances. These data highlight the importance of separating genetic RIP3 deficiency from RIP1 inhibition by Nec-1 application in vivo and challenge the current definition of necroptosis.