Development Of Multiorgan Failure Research Articles

COVID-19-Triggered Acute Liver Failure and Rhabdomyolysis: A Case Report and Review of the Literature

COVID-19 is primarily known for its respiratory tract involvement, often leading to severe pneumonia and exacerbation of underlying diseases. However, emerging evidence suggests that COVID-19 can result in multiorgan failure, affecting organs beyond the respiratory system. We present the case of a 62-year-old male with COVID-19 who developed acute liver failure (ALF) and rhabdomyolysis in the absence of respiratory failure. Initially, the patient presented with significantly elevated aspartate transaminase (5398 U/L) and alanine transaminase (2197 U/L) levels. Furthermore, a prolonged prothrombin time international normalized ratio (INR) of 2.33 indicated the diagnosis of ALF without hepatic coma, according to Japanese diagnostic criteria. The patient also exhibited elevated creatine kinase (9498 U/L) and a mild increase in creatinine (1.25 mg/dL) levels, but both values improved with intravenous fluid support and molnupiravir administration. To our knowledge, this is the first reported case presenting with both ALF and rhabdomyolysis associated with COVID-19. In addition, we review the existing literature to summarize previously reported cases of ALF triggered by SARS-CoV-2. This case report underscores the significance of recognizing COVID-19 as a significant contributing factor in the development of multiorgan failure. Furthermore, it suggests that COVID-19 can lead to severe illness, irrespective of the absence of respiratory failure.

1851-PUB: Intractable Diabetic Ketoacidosis with Enfortumab Vedotin

Enfortumab Vedotin (EV) is an antibody-drug conjugate for metastatic urothelial carcinoma. Hyperglycemia and diabetic ketoacidosis (DKA) have been reported in patients using EV. The incidence increases with higher BMI. The one case report available on the association between EV and DKA resulted in development of multiorgan failure and death. This case, however, describes a positive outcome with recovery from DKA. We present a case of a 59 year-old Caucasian woman with morbid obesity, prediabetes and recurrent metastatic urothelial cell carcinoma who presented with hyperglycemia after 2 doses of EV. Labs were indicative of DKA without an infectious etiology. She was admitted to the ICU for intravenous insulin drip treatment. Hyperglycemia and ketosis persisted despite using a maximum insulin drip rate of 60 units/hour. Starvation ketosis was a factor, so a diet was started. On day 2, NPH insulin and prandial lispro were added along with the insulin drip, resulting in a total daily insulin dose of 1660 units. Nevertheless, hyperglycemia persisted. U-500 regular insulin was initiated and by day 4, the patient received a total of 2940 units of insulin in one day with normalized serum ketones. Insulin drip requirements decreased with blood glucose controlled solely on subcutaneous insulin. She remained euglycemic, so U-500 insulin was switched to daily glargine. Eventually, she was off all insulin and maintained blood glucose below 130 mg/dL. Work up for insulin resistance included a C-peptide of 42.6 ng/mL (normal 1.1-4.4) with glucose of 230 mg/dL, negative glutamic acid decarboxylase 65 and insulin antibodies, and a glucagon level of 213 pg/mL (normal ≤80) with glucose of 220 mg/dL. Although the mechanism by which EV causes hyperglycemia is not known, this case illustrates that hyperglycemia was due to severe insulin resistance associated with EV. Understanding this, along with glycemic effects of targeted therapies with Vedotin are necessary to investigate the causal mechanism and treatment for EV related hyperglycemia/DKA. Disclosure A.Elahi: None. J.Duron: None. T.Porter: None.

S2275 Black Esophagus Due to Severe SARS-CoV2 Infection

Introduction: Acute esophageal necrosis (AEN), also called ‘black esophagus’ due to its appearance is a rare clinical disease, recently described in medical literature. The etiology is multifactorial, often in the setting of severe systemic conditions such as sepsis and trauma, and outcomes are poor. Severe SARS-CoV2 infection can lead to overwhelming inflammation and multi-organ failure. Herein, we present a case of black esophagus with severe SARS-CoV2 infection. Case Description/Methods: A 69-year-old with rheumatoid disease, on immune suppression, was admitted to our hospital with dyspnea, coffee ground emesis and melena. He tested positive for SARS-CoV2 and was found to have acute blood loss anemia. An urgent EGD was performed which revealed a black, necrotic mucosa of the distal 2/3rd of the esophagus, consistent with AEN. Biopsies were avoided due to risk of perforation and subsequent images were negative for any perforation. Management was started with high dose PPI and supportive care in addition to recognized treatment for COVID-19. However, his hospital stay became complicated with progressive clinical decline and development of multi-organ failure. Eventually, he was transitioned to comfort care and passed away shortly after (Figure). Discussion: AEN or black esophagus, as defined by its endoscopic appearance, is a manifestation of ischemic and corrosive injury to the esophagus in the setting of severe systemic disease processes. Diffuse, circumferential, necrotic and friable esophageal mucosa, especially in the distal 2/3rd, is the hallmark. The relatively poor vascular supply of the distal esophagus makes it more susceptible to such injury. Often, a sharp demarcation is seen at the Z-line. Histology shows extensive transmural necrosis. Pathogenesis of AEN is thought to be a combination of a sudden low flow, prothrombotic state from severe systemic illness causing ischemic injury and impaired healing ability. At the same time, increased exposure to gastric content occurs from gastric hypokinesis and increased secretions which exacerbate injury. Typical presentation is upper GI bleed, and management revolves around treatment of underlying etiology and supportive measures with acid suppression and mucosal protection with PPI and sucralfate. NG tubes should be avoided due to risk of perforation, which is the most serious complication. Surgical intervention is reserved for perforation, and balloon dilation can be required in cases of stenosis or strictures.Figure 1.: Diffuse necrotic appearing esophagus with black discoloration on EGD Dilated esophagus with diffuse esophageal wall thickening on CT.

Diagnostic efficacy of C-reactive protein and IL-6 as markers of systemic inflammation

Currently, despite widespread use of the terms systemic inflammation (SI) and systemic inflammatory response (SIR), there are no generally accepted criteria for their verification. These processes are often identified (which is methodologically incorrect) and associated with an increase in pro-inflammatory mediators in the blood. However, SI is a complex process that requires integral criteria including assessment of SIR as reactivity level, and additional SI phenomena, such as microthrombosis, systemic alteration, and distress of the neuroendocrine system. At the same time, there is a need to assess individual CB indicators as a more affordable alternative for medical practice than the use of complex integral indicators. Our objective was to evaluate diagnostic efficacy of CRP and IL-6 levels as markers of acute and chronic systemic inflammation.
 The data of patients with acute critical conditions of infectious and non-infectious genesis were analyzed to study acute systemic inflammation (SI), data of patients with autoimmune diseases, chronic organ failure and other chronic destructive diseases were analyzed to study chronic systemic inflammation (ChrSI). SIR severity was evaluated by the calculation of an integral index reactivity level (RL). Differentiation of the inflammatory process to either classical inflammation (CI), or systemic inflammation was carried out using the previously proposed scale of SI, verification of chronic systemic inflammation was performed by means of ChrSI scale. SI (or ChrSI) was revealed in all groups of patients, and the frequency of SI registration in patients with acute conditions increased with development of multi-organ failure. The frequency of SIR was higher in all groups, thus confirming inability to equate these disorders. ROC analysis showed that CRP level had poor diagnostic efficacy on the development of SI/ChrSI (AUC 0.6), and IL-6 level had very good diagnostic value (AUC 0.8-0.9). The prognostic value of the markers for detecting the SIR was higher, with AUCIL-6 exceeding AUCCRP. Thus, IL-6 in many acute and chronic pathologies is sufficiently closer to integral indices than C-reactive protein with respect to diagnostic efficiency, and the dynamics of IL-6 in blood may be used to predict and evaluate complications associated with acute and chronic SI, as well as to prescribe and monitor the results of anticytokine therapy.

Fulminant myocarditis in adults: a narrative review.

Fulminant myocarditis (FM) is an uncommon syndrome characterized by sudden and severe hemodynamic compromise secondary to acute myocardial inflammation, often presenting as profound cardiogenic shock, life-threatening ventricular arrhythmias and/or electrical storm. FM may be refractory to conventional therapies and require mechanical circulatory support (MCS). The immune system has been recognized as playing a pivotal role in the pathophysiology of myocarditis, leading to an increased focus on immunosuppressive treatment strategies. Recent data have highlighted not only the fact that FM has significantly worse outcomes than non-FM, but that prognosis and management strategies of FM are heavily dependent on histological subtype, placing greater emphasis on the role of endomyocardial biopsy in diagnosis. The impact of subtype on severity and prognosis will likewise influence how aggressively the myocarditis is managed, including whether MCS is warranted. Many patients with refractory cardiogenic shock secondary to FM end up requiring MCS, with venoarterial extracorporeal membrane oxygenation demonstrating favorable survival rates, particularly when initiated prior to the development of multiorgan failure. Among the challenges facing the field are the need to more precisely identify immunopathophysiological pathways in order to develop targeted therapies, and the need to better optimize the timing and management of MCS to minimize complications and maximize outcomes.

Mesenchymal stem cell extracellular vesicles mitigate vascular permeability and injury in the small intestine and lung in a mouse model of hemorrhagic shock and trauma.

Hemorrhagic shock and trauma (HS/T)-induced gut injury may play a critical role in the development of multi-organ failure. Novel therapies that target gut injury and vascular permeability early after HS/T could have substantial impacts on trauma patients. In this study, we investigate the therapeutic potential of human mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (MSC EVs) in vivo in HS/T in mice and in vitro in Caco-2 human intestinal epithelial cells. In vivo, using a mouse model of HS/T, vascular permeability to a 10-kDa dextran dye and histopathologic injury in the small intestine and lungs were measured among mice. Groups were (1) sham, (2) HS/T + lactated Ringer's (LR), (3) HS/T + MSCs, and (4) HS/T + MSC EVs. In vitro, Caco-2 cell monolayer integrity was evaluated by an epithelial cell impedance assay. Caco-2 cells were pretreated with control media, MSC conditioned media (CM), or MSC EVs, then challenged with hydrogen peroxide (H2O2). In vivo, both MSCs and MSC EVs significantly reduced vascular permeability in the small intestine (fluorescence units: sham, 456 ± 88; LR, 1067 ± 295; MSC, 765 ± 258; MSC EV, 715 ± 200) and lung (sham, 297 ± 155; LR, 791 ± 331; MSC, 331 ± 172; MSC EV, 303 ± 88). Histopathologic injury in the small intestine and lung was also attenuated by MSCs and MSC EVs. In vitro, MSC CM but not MSC EVs attenuated the increased permeability among Caco-2 cell monolayers challenged with H2O2. Mesenchymal stem cell EVs recapitulate the effects of MSCs in reducing vascular permeability and injury in the small intestine and lungs in vivo, suggesting MSC EVs may be a potential cell-free therapy targeting multi-organ dysfunction in HS/T. This is the first study to demonstrate that MSC EVs improve both gut and lung injury in an animal model of HS/T.

Effects of β-Blockers on the Sympathetic and Cytokines Storms in Covid-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a causative virus in the development of coronavirus disease 2019 (Covid-19) pandemic. Respiratory manifestations of SARS-CoV-2 infection such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) leads to hypoxia, oxidative stress, and sympatho-activation and in severe cases leads to sympathetic storm (SS). On the other hand, an exaggerated immune response to the SARS-CoV-2 invasion may lead to uncontrolled release of pro-inflammatory cytokine development of cytokine storm (CS). In Covid-19, there are interactive interactions between CS and SS in the development of multi-organ failure (MOF). Interestingly, cutting the bridge between CS and SS by anti-inflammatory and anti-adrenergic agents may mitigate complications that are induced by SARS-CoV-2 infection in severely affected Covid-19 patients. The potential mechanisms of SS in Covid-19 are through different pathways such as hypoxia, which activate the central sympathetic center through carotid bodies chemosensory input and induced pro-inflammatory cytokines, which cross the blood-brain barrier and activation of the sympathetic center. β2-receptors signaling pathway play a crucial role in the production of pro-inflammatory cytokines, macrophage activation, and B-cells for the production of antibodies with inflammation exacerbation. β-blockers have anti-inflammatory effects through reduction release of pro-inflammatory cytokines with inhibition of NF-κB. In conclusion, β-blockers interrupt this interaction through inhibition of several mediators of CS and SS with prevention development of neural-cytokine loop in SARS-CoV-2 infection. Evidence from this study triggers an idea for future prospective studies to confirm the potential role of β-blockers in the management of Covid-19.

COVID-19 Infection and Outcomes at a Comprehensive Sickle Cell Center

Introduction: The Grady Comprehensive Sickle Cell (SC) center is the largest adult sickle cell center in the United States (US) and has the first 24/7 acute care unit for management of sickle cell vaso-occlusive events (VOE). In 2019, the center provided 3077 sickle cell outpatient visits and 3695 acute care visits. When the COVID-19 pandemic reached the US, the center had a precipitous drop in the number of both outpatient clinic and acute care visits as state regulations for lockdown were passed. This report follows all the COVID-19 cases at a single adult center for sickle cell disease in one year.Methods: The clinical database has been tracking COVID-19 cases reported. Out of a total of 1343 patients, 55 patients contracted COVID-19 and were tracked in the clinical database with IRB approval.Results: Of the 55 patients with COVID-19, 28 were female and 27 were male. By genotype, 64% of patients were SS, 31% were SC and 5% were Sβ+ thalassemia. 35% of patient were on hydroxyurea for disease modification with the majority of them being of the SS genotype and 31% had elevated fetal hemoglobin determined by a percentage fetal hemoglobin above 5% by hemoglobin electrophoresis. Chronic pain (defined as patients experiencing daily pain episodes for more than 4 days a week for the last 3 months) and calculation of daily morphine equivalents were reported in clinic follow-up and the narcotic database utilization. 47% of the patients had chronic pain and the median morphine equivalents was 90 mg daily (45-225mg).The rate of emergency department (ED) visits or hospitalizations for the sickle cell patients with COVID-19 was 80%. 49% of the SC patients' visits were related to VOE and 27% related to COVID-19 primarily. 20% of SC patients with COVID-19 were not seen in any emergency setting or required any hospitalization.The COVID-19 signs and symptoms experienced by the patients were as follows: 58% had pain as the main presenting symptom, followed by cough and fever (40%), dyspnea (31%), and pneumonia with chest x-ray evidence (25%). 2 patients developed acute respiratory distress syndrome (ARDS) and were intubated, and 2 patients died. 29% of the patients had lung findings on imaging and 16 of 55 patients required treatment with the use of Remdesivir in 9, dexamethasone in 8 and red cell products in 7 of the 16 patients. The 2 patients who died had both presented with COVID-19 infection in June and July 2020 respectively. One patient had presented in June 2020 with VOE and was found to have bilateral lung opacities but was asymptomatic and was discharged home to return few days later with clinical picture of multi-organ failure for which a red cell erythrocytapheresis was attempted. The second patient had presented in July 2020 with COVID-19 pneumonia and was treated with Remdesivir and convalescent plasma with development of multi-organ failure and ARDS.Discussion:Several reports were published regarding the rate of COVID-19 related mortality and morbidity in sickle cell disease. The Grady comprehensive sickle cell center experience differs in the fact that 16 out of 55 patients who had contracted COVID-19 required treatment and 2 of those 16 had died. In fact, the deaths occurred early in the course of the pandemic in June and July 2020 when 20 total cases were diagnosed (from March to Septemeber 2020). The remaining 35 cases registered zero deaths (October 2020 to March 2021) with the rate of complicated COVID-19 hospitalizations decreasing with better treatment available. In addition, the timeline for the COVID-19 cases reported fits the population timeline of 2 peaks respectively happening in the summer of 2020 and the Winter of 2021. During the initial peak, we have noted a decrease in the number of clinic and acute care visits respectively. This was anticipated given the statewide lockdown that was implemented. To circumvent that, the center adopted virtual visits to deliver healthcare needs. This measure has aided in protecting patients against COVID-19. Additionally, it is interesting that despite the second peak in the winter of 2021, there were no reported deaths among the patients who developed COVID-19. This finding can suggest that despite the concern for morbidity and mortality of sickle cell patients, their diligence and awareness to stay home during the pandemic has proven crucial in reducing morbidity and mortality and the option of virtual visits for healthcare delivery was key and should be utilized further in sickle cell care. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Non-anaesthetic effects of modern halogen-containing anaesthetics

Many patients undergo surgery under general anaesthesia each day. One of the high-priority tasks for an anesthesiologist is to protect tissues from a systemic inflammatory reaction or oxidative distress (including ischaemia/reperfusion). This review aims to demonstrate the anti-inflammatory and antioxidant properties of general anaesthesia in experimental and clinical studies.Halogenated anaesthetics lead to the inactivation of glycogen synthase kinase-3β (GSK-3β), a key enzyme in the implementation of cellular damage mechanisms and systemic inflammatory response syndrome (SIRS). These mechanisms are implemented through the transcription factor nuclear factor (NF)-κB. As a result of NF-κB activation, gene expression responsible for proinflammatory cytokine synthesis follows, activating leukocytes and disrupts endothelial cell junctions, leading to a disruption of the endothelial barrier, leukocyte infiltration into tissues, and the development of SIRS. Furthermore, GSK-3β phosphorylation causes an increase in the level in neuronal cells and hepatocytes of transcription factor Nrf2, which is a master regulator of enzyme levels of antioxidant defence in the cell.Thus, halogenated anaesthetics interfere with different elements responsible for the implementation of SIRS and oxidative distress in addition to limiting disturbing factors during the development of multiorgan failure and endothelial dysfunction in experimental sepsis and a model of ischaemia/reperfusion. Understanding these processes can help to reduce many complications during the post-operative period.Received 9 January 2020. Revised 6 April 2020. Accepted 7 April 2020.Funding: The study did not have sponsorship.Conflict of interest: Authors declare no conflict of interest.Author contributionsConception and study design: O.A. Grebenchikov, Y.V. Skripkin, V.V. Likhvantsev Drafting the article: O.A. Grebenchikov, Y.V. Skripkin, O.N. Gerasimenko, K.K. Kadantseva, A.L. Bachinskiy, L.B. Berikashvili, V.V. Likhvantsev Critical revision of the article: О.А. Grebenchikov, K.K. Kadantseva Final approval of the version to be published: O.A. Grebenchikov, Y.V. Skripkin, O.N. Gerasimenko, K.K. Kadantseva, A.L. Bachinskiy, L.B. Berikashvili, V.V. Likhvantsev

Decreased endothelial glycocalyx thickness is an early predictor of mortality in sepsis.

Microcirculatory alterations play an important role in the early phase of sepsis. Shedding of the endothelial glycocalyx is regarded as a central pathophysiological mechanism causing microvascular dysfunction, contributing to multiple organ failure and death in sepsis. The objective of this study was to investigate whether endothelial glycocalyx thickness at an early stage in septic patients relates to clinical outcome. We measured the perfused boundary region (PBR), which is inversely proportional to glycocalyx thickness, of sublingual microvessels (5–25 µm) using sidestream dark field imaging. The PBR in 21 patients with sepsis was measured within 24 h of admission to the intensive care unit (ICU). In addition, we determined plasma markers of microcirculatory dysfunction and studied their correlation with PBR and mortality. Endothelial glycocalyx thickness in sepsis was significantly lower for non-survivors as compared with survivors, indicated by a higher PBR of 1.97 [1.85, 2.19]µm compared with 1.76 [1.59, 1.97] µm, P=0.03. Admission PBR was associated with hospital mortality with an area under the curve of 0.778 based on the receiver operating characteristic curve. Furthermore, PBR correlated positively with angiopoietin-2 (rho=0.532, P=0.03), indicative of impaired barrier function. PBR did not correlate with Acute Physiology and Chronic Health Evaluation IV (APACHE IV), Sequential Organ Failure Assessment score (SOFA score), lactate, syndecan-1, angiopoietin-1 or heparin-binding protein. An increased PBR within the first 24 h after ICU admission is associated with mortality in sepsis. Further research should be aimed at the pathophysiological importance of glycocalyx shedding in the development of multi-organ failure and at therapies attempting to preserve glycocalyx integrity.

Liver Disease and Hemostasis (Review) Part 2. Cholestatic Liver Disease and Hemostasis

The presence or development of liver disorders can significantly complicate the course of critical illness and terminal conditions. Systemic hemostatic disorders are common in Intensive Care Units patients with cholestatic liver diseases, so the study of the mechanisms of their development can contribute to the understanding of the development of multiorgan failure in critical illness.The review discusses current data on changes in hemostatic parameters in patients with cholestatic liver diseases, proposes a mechanism for the development of such disorders, which involve interactions of phospholipids with platelet and endotheliocyte membranes. It is suggested that a trend for thrombosis in patients with cholestatic liver disease is due to increased accumulation of bile acids in the systemic circulation. Available data demonstrate that the antiphospholipid syndrome may predispose to the formation of blood clots due to alterations of phospholipid composition of membranes of platelets and vascular endothelial cells by circulating antiphospholipid antibodies. Clarifying the mechanisms contributing to changes of the blood coagulation system parameters in liver disorders will aid to development of optimal correction of hemostatic disorders in patients with chronic liver diseases.

Mitochondrial Function in the Kidney and Heart, but Not the Brain, is Mainly Altered in an Experimental Model of Endotoxaemia.

Significant impairments in mitochondrial function are associated with the development of multi-organ failure in sepsis/endotoxaemia, but the data on the dynamics of simultaneous mitochondrial impairment in multiple organs are limited. The aim of this study was to evaluate the changes in heart, brain and kidney mitochondrial function in an experimental model of lipopolysaccharide (LPS)-induced endotoxaemia.Samples were collected 4 and 24 h after single injection of LPS (10 mg/kg) in mice. Marked increases in inflammation-related gene expression were observed in all studied tissues 4 h after LPS administration. At 24 h post LPS administration, this expression of inflammation-related genes remained upregulated only in kidneys. Significantly increased concentrations of kidney function markers confirmed that kidneys were severely damaged. Echocardiographic measurements showed that the ejection fraction and fractional shortening were significantly reduced 4 h after LPS administration, whereas 24 h after LPS administration, the cardiac function was restored to baseline. A two-fold decrease in mitochondrial oxidative phosphorylation (OXPHOS) capacity in the kidney was observed 4 and 24 h after LPS administration. Significant decrease in mitochondrial fatty acid oxidation was observed in heart 4 h after LPS administration. Furthermore, 24 h after LPS administration, the respiration rates in cardiac fibers at OXPHOS and electron transport (ET) states were significantly increased, which resulted in increased ET coupling efficiency in the LPS-treated group, whereas four-fold increases in the H2O2 production rate and H2O2/O ratio were observed. The brain mitochondria demonstrated a slightly impaired mitochondrial functionality just 24 h after the induction of endotoxaemia.In conclusion, among studied tissues kidney mitochondria are the most sensitive to endotoxaemia and do not recover from LPS-induced damage, whereas in brain, mitochondrial function was not significantly altered. In heart, endotoxaemia induces a decrease in the mitochondrial fatty acid oxidation capacity, but during the phase of suppressed inflammatory response, the ET efficiency is improved despite the marked increase in reactive oxygen species production.

Surgical management of spine injuries in severe polytrauma patients: a retrospective study

Background: Optimal surgical management of spinal injuries as part of life-threatening multiple traumas remains challenging. We provide insights into the surgical management of spinal injuries in polytrauma patients. Methods: All patients from our polytrauma care network who both met at least one positive Vittel criteria and an injury severity score (ISS) >15 at admission and who underwent surgery for a spinal injury were included retrospectively. Demographic data, clinical data demonstrating the severity of the trauma and imaging defining the spinal and extraspinal number and types of injuries were collected.Results: Between January 2012 and December 2016, 302 (22.2%) patients suffered from spinal injury (143 total injuries) and 83 (6.1%) met the inclusion criteria. Mean ISS was 36.2 (16–75). Only 48 (33.6%) injuries led to neurological impairment involving the thoracic (n = 23, 16.1%) and lower cervical (n = 15, 10.5%) spine. The most frequent association of injuries involved the thoracic spine (n = 42). 106 spinal surgeries were performed. The 3-month mortality rate was 2.4%.Conclusions: We present data collected on admission and in the early postoperative period referring to injury severity, the priority of injuries, and development of multi-organ failure. We revealed trends to guide the surgical support of spinal lesions in polytrauma patients.

2257 Hepatic Dysfunction as a Result of Multiple Myeloma

INTRODUCTION: Plasma cell infiltration of the liver can be detected in up to 45% of patients with multiple myeloma (MM) at autopsy. However, only a few cases have been reported of plasma cell infiltration of the liver leading to plasmacytoma formation and non-obstructive cholestasis with progression to liver failure. CASE DESCRIPTION/METHODS: A 53-year-old African American male with history of IgG multiple myeloma status post AlloimmuneStem Cell transplant (ASCT) in 2010 was admitted for intermittent epistaxis, hemoptysis and fatigue found to have relapse. Patient was started on salvage therapy with bortezomib, dexamethasone, cyclophosphamide, etoposide and cisplatin (VDCEP). Physical exam revealed an alert and lethargic male in no acute distress but with asterixis. Sclera were icteric. Abdominal exam revealed marked hepatomegaly without tenderness. Laboratory data showed an ALT of 60 IU/L, total bilirubin of 11mg/dL and normal AST and ALP . INR was 3.0, platelets 38 × 103 mcL, Hgb 7.6gm/dL and WBC 1.6 × 103 mcL. Factor VIII activity was 311.1%. Ammonia levels were 67mcmol/L. Imaging with MRI showed an enlarged liver measuring 22.4cm without mass lesions. A transjugular liver biopsy was then performed revealing atypical mononuclear cell infiltration with positive stain for CD138 and MUM1 consistent with patient’s known history of labda-restricted plasma cell neoplasm (Figures 1 and 2). His clinical course deteriorated with worsening total bilirubin, hepatic encephalopathy and coagulopathy consistent with liver dysfunction and acute liver failure. Eventually there was development of multiorgan failure and death. Autopsy confirmed presence of myeloma cells in the liver forming a subcapsular plasmacytoma with associated extensive cholestasis and hepatocyte necrosis. DISCUSSION: Hepatic involvement of multiple myeloma most commonly presents with hepatomegaly and portends poor prognosis. It is important to recognize that patients may present with a cholestatic pattern of liver injury which can lead to severe hepatic dysfunction and liver failure such as the case of our patient. The histological pattern of liver involvement in MM can be in the form of light chain deposition disease, extramedullary plasmacytoma, amyloidosis, or a diffuse infiltrative pattern. Liver biopsy is thus an imperative way of diagnosis particularly to differentiate it from other entities causing similar pattern of injury such as sinusoidal occlusive syndrome or drug induced liver injury.

83 The Pancreatitis Activity Scoring System Predicts Post-Intervention Outcomes and Early Readmission in Patients With Infected Pancreatic Necrosis

INTRODUCTION: The Pancreatitis Activity Scoring System (PASS) score comprises of five weighted components (organ failure, SIRS, abdominal pain, opiate requirement, and oral intake), and has been externally validated to predict readmission and development of moderate to severe acute pancreatitis (AP). Our aim was to study the predictive role of PASS score (PS) in patients with suspected or confirmed infected pancreatic necrosis (IPN). METHODS: Consecutive inpatients with IPN requiring intervention treated at UCSF January 2011 through January 2019 were identified. PSs were calculated at admission, prior to and 72-hours after each intervention, and at discharge. Multivariable logistical regression was used to assess the relationship between PS and various outcomes; development of multi-organ failure (MOF), need for early re-intervention (<1 week) and 30-day readmission. RESULTS: 67 patients (median age 54) were identified; organ failure rates were 55% respiratory, 60% shock, and 72% renal. Median admission PS was 440 (IQR 345–605). 38 patients underwent surgical therapy and 29 underwent step-up endoscopic therapy; median admission PSs were similar (405 vs 460, P = 0.62). A 20% reduction in the baseline PS at 72 hours post-intervention was associated with a lower rate of MOF development (aOR 0.01; 95% CI: 0.001–0.13, P < 0.001) and early re-intervention (aOR 0.03; 95% CI: 0.003–0.16, P < 0.001). The 72-hour post-intervention PS (AUC = 0.88) was superior to admission PS, post-intervention SIRS or pain score (AUC = 0.66, 0.51, 0.43, respectively P < 0.001) for the prediction of development of MOF. Discharge PS < 250 was associated with 89% lower odds of 30-day readmission (aOR 0.11; 95% CI: 0.03–0.46, P = 0.002) and the discharge PS (AUC = 0.88, Figure 1) had superior prediction of readmission compared to discharge pain or admission PASS scores (AUC = 0.66 and 0.60, respectively P < 0.001). CONCLUSION: In this retrospective cohort study, the PASS score was associated with post-intervention clinical outcomes and early readmission suggesting it is a valid measure of disease activity in patients with infected pancreatic necrosis. Prospective studies are needed to further validate these results.

Mesenchymal stromal cells to protect kidney after traumatic hemorrhagic shock

Background & Aim Haemorrhagic shock (HS) refers to the inadequate perfusion of tissues due to the imbalance between systemic oxygen delivery and consumption. Blunt or penetrating trauma is the most common cause of HS. The development of multiorgan failure after severe trauma is one of the leading causes of morbidity and late mortality. Among critical organs, the Acute Kidney Injury (AKI) affects up to 50% of the patients and no etiologic treatment is available. Mesenchymal Stromal Cells (MSC) are multipotent cells found in a large number of adult tissues and used in clinical practice as a therapeutic agent for immunomodulation and tissue repair. Many studies have highlighted their immunomodulatory, anti-apoptotic/anti-oxidative stress, pro-angiogenic effect, stimulation of endogenous regenerative process or anti-fibrotic effect by direct contact or by secreting bioactive molecules. Our objective was to evaluate and optimize an early MSC therapy after traumatic hemorrhagic shock (THS) inducing an AKI. Methods, Results & Conclusion We have developed in vivo THS model and validated functional assays on cultures of immune and renal human cells. In vivo, rats were subjected to 1h of HS at a Mean Arterial Pressure of 30mmHg, associated with administration of 1ml plasma from THS animals. Biological and histological analyses are currently performed on D2, D7 and D21. In vitro, a cellular model of renal injury was developed by adding a "shock cocktail" (SC) containing inflammatory cytokines, HMGB1, histones and H2O2. Several criteria have been studied: Membrane polarization of the mitochondria by the JC1 dye, MitoSOX and CellROX probes to evaluate the mitochondrial and cytoplasmic oxidation state. Aggression of renal cells induced a decrease in the mitochondrial membrane polarization. The CellROX probe also showed an increase in cytoplasmic oxidative stress. We also developed a model of inflammation using THP1 cell line treated with SC. The SC induced an increase in TNFα secretion by THP1. Our main preliminary results indicated that MSCs improved the viability of renal cells, partially restored their mitochondrial membrane potential and decreased their cytoplasmic oxidative stress. In addition, they can exert an anti-inflammatory effect by inhibited the secretion of TNFα by THP1 and increased their secretion of the anti-inflammatory cytokine IL1RA. Finally, the pre-clinical model mimicking a polytrauma could be a formidable tool to evaluate the benefit of MSC therapy, away from shock. Haemorrhagic shock (HS) refers to the inadequate perfusion of tissues due to the imbalance between systemic oxygen delivery and consumption. Blunt or penetrating trauma is the most common cause of HS. The development of multiorgan failure after severe trauma is one of the leading causes of morbidity and late mortality. Among critical organs, the Acute Kidney Injury (AKI) affects up to 50% of the patients and no etiologic treatment is available. Mesenchymal Stromal Cells (MSC) are multipotent cells found in a large number of adult tissues and used in clinical practice as a therapeutic agent for immunomodulation and tissue repair. Many studies have highlighted their immunomodulatory, anti-apoptotic/anti-oxidative stress, pro-angiogenic effect, stimulation of endogenous regenerative process or anti-fibrotic effect by direct contact or by secreting bioactive molecules. Our objective was to evaluate and optimize an early MSC therapy after traumatic hemorrhagic shock (THS) inducing an AKI. We have developed in vivo THS model and validated functional assays on cultures of immune and renal human cells. In vivo, rats were subjected to 1h of HS at a Mean Arterial Pressure of 30mmHg, associated with administration of 1ml plasma from THS animals. Biological and histological analyses are currently performed on D2, D7 and D21. In vitro, a cellular model of renal injury was developed by adding a "shock cocktail" (SC) containing inflammatory cytokines, HMGB1, histones and H2O2. Several criteria have been studied: Membrane polarization of the mitochondria by the JC1 dye, MitoSOX and CellROX probes to evaluate the mitochondrial and cytoplasmic oxidation state. Aggression of renal cells induced a decrease in the mitochondrial membrane polarization. The CellROX probe also showed an increase in cytoplasmic oxidative stress. We also developed a model of inflammation using THP1 cell line treated with SC. The SC induced an increase in TNFα secretion by THP1. Our main preliminary results indicated that MSCs improved the viability of renal cells, partially restored their mitochondrial membrane potential and decreased their cytoplasmic oxidative stress. In addition, they can exert an anti-inflammatory effect by inhibited the secretion of TNFα by THP1 and increased their secretion of the anti-inflammatory cytokine IL1RA. Finally, the pre-clinical model mimicking a polytrauma could be a formidable tool to evaluate the benefit of MSC therapy, away from shock.

Effect of 3-mercaptopyruvate Sulfurtransferase Deficiency on the Development of Multiorgan Failure, Inflammation, and Wound Healing in Mice Subjected to Burn Injury.

The gaseous transmitter hydrogen sulfide (H2S) has been implicated in various forms of critical illness. Here, we have compared the outcome of scald burn injury in wild-type mice and in mice deficient in 3-mercaptopyruvate sulfurtransferase (3-MST), a mammalian H2S-generating enzyme. Outcome variables included indices of organ injury, clinical chemistry parameters, and plasma levels of inflammatory mediators. Plasma levels of H2S significantly increased in response to burn in wild-type mice, but remained unchanged in 3-MST-/- mice. The capacity of tissue homogenates to produce H2S from 3-mercaptopyruvate was unaffected by burn injury. In 3-MST-/- mice, compared to wild-type controls, there was a significant enhancement in the accumulation of polymorphonuclear cells (as assessed by the quantification of myeloperoxidase) in the liver (but not heart, lung, or skin) at 7 days postburn. Oxidative tissue damage (as assessed by malon dialdehyde content) was comparable between wild-type and 3-MST-deficient mice in all tissues studied. 3-MST-/- and wild-type mice exhibited comparable burn-induced elevations in circulating plasma levels of hepatic injury; however, 3-MST-/- mice exhibited a higher degree of renal injury (as reflected by elevated blood urea nitrogen levels) at 7 days postburn. Inflammatory mediators (eg, TNF-α, IL-1β, IL-2, IL-6, IL-10, and IL-12) increased in burn injury, but without significant differences between the 3-MST-/- and wild-type groups. The healing of the burn wound was also unaffected by 3-MST deficiency. In conclusion, the absence of the H2S-producing enzyme 3-MST slightly exacerbates the development of multiorgan dysfunction but does not affect inflammatory mediator production or wound healing in a murine model of burn injury.

Acute on chronic liver failure - Clinical profile, precipitating factors, outcome and predictors of mortality

INTRODUCTION : Liver failure can develop acutely in a patient with no preexisting liver disease (Acute Liver Failure) or as an acute decompensation of a chronic liver disease. Recently it has been noted that a subgroup of patients develops acute deterioration in previously compensated cirrhosis and are considered to have acute on chronic liver failure (ACLF). This deterioration is secondary to an acute event and multi organ failure leading to increased mortality at three months. In contrast to chronic liver disease these patients have a rapid downhill course with the development of multiorgan failure and high short term mortality. One important concept in this group of patients is the potential reversibility. The term reversibility does not mean that underlying chronic liver damage is reversible, but rather the acute deterioration of the liver function due to the precipitating event is reversible. The pathophysiological basis ACLF was initially described by Jalan [et al.]. There is no clear cut definition of ACLF in the western literature. Asia Pacific association of study of liver (APASL) has defined it as acute hepatic insult manifested by jaundice and coagulopathy complicated within four weeks by ascites or encephalopathy. The cause for acute deterioration can vary from infectious causes like sepsis, viral hepatitis and non hepatotrophic viruses’ infection or noninfectious causes like alcohol, drugs, gastrointestinal bleeding, toxins and surgery. There is controversy 2 regarding whether sepsis can precipitate ACLF or it is the result of ACLF. Though numerous studies have been published in western literature on cirrhotic patients admitted to ICU, most of them have not differentiated organ failure as part of progressive worsening in end stage cirrhosis from acute on chronic liver failure. There are very few studies from India in this subject. H Garg [et al.] have recently published a prospective study on ACLF patients. Etiology of chronic liver disease and the acute precipitants differ between various geographical locations. AS ACLF carries a high mortality it is essential to identify prognostic factors. In general it has been noted that score evaluating the severity of disease like APACHE and SOFA score are better than liver specific score like Child Pugh score. Management of ACLF requires good intensive care to prevent the development of organ failure or to support the failing organs. Use of various extracorporeal liver support systems have been studied in various studies. Even though there is an improvement in biochemical parameters and in hepatic encephalopathy ,there is no significant survival benefit. Liver transplantation is the only curative treatment. This prospective study aims to look at the clinical profile, precipitating factors, outcome prognostic factors in ACLF admitted in a tertiary care hospital. AIM OF THE STUDY : The aims of the study are as follows, 1. To study the clinical profile of patients with acute on chronic liver failure, 2. To study the underlying chronic aetiology and acute precipitants, 3. To study the 30 day and 90 day mortality, 4. To study the various predictors of mortality. CONCLUSION : Acute on chronic liver failure is a unique entity. It is characterized by rapidly deteriorating course in a previously diagnosed or undiagnosed chronic liver disease with a potential for reversibility. Our study shows that it has high short term mortality (44%). Most common aetiology for underlying chronic liver disease in our centre is alcoholic liver disease (64.5%) followed by hepatitis B (20%) and other causes. The most common acute precipitant is super added alcoholic hepatitis (82%) in alcoholic liver disease and reactivation of hepatitis B (66%) in chronic hepatitis B. Other causes of acute worsening include acute hepatitis E and drug induced liver injury. Most common cause of death is the multi organ failure. Increasing number of organ failures is associated with increasing risk of death. High serum bilirubin, high INR, renal failure, low sodium, and high CRP are all poor prognostic markers. SOFA and MELD are better predictors of mortality than Child score. Early referral for liver transplantation is essential in patients at high risk of death. Acute on chronic liver failure is a disease which is still being defined and large prospective studies are needed to better delineate the acute precipitants and the prognostic markers.

Lung-protective Ventilation for Acute Respiratory Distress Syndrome.

Lung-protective Ventilation for Acute Respiratory Distress Syndrome.

Oxandrolone protects against the development of multiorgan failure, modulates the systemic inflammatory response and promotes wound healing during burn injury

Oxandrolone is a synthetic oral non-aromatizable testosterone derivative. This drug has been used successfully for several decades to safely treat growth delays in various diseases including Turner’s syndrome. Currently the use of oxandrolone is under clinical testing in children with burn injury; the available data indicate that the anabolic steroid increases net muscle protein balance, maintains lean body mass, and reduces intensive care unit stay. Although oxandrolone is already in clinical trials in burn patients, preclinical burn-related studies with oxandrolone – especially those that go beyond muscle-related parameters and focus on burn-associated organ dysfunction, inflammatory response and wound healing – remain to be conducted. In the current project, using a well-characterized murine model of third-degree burn, we have tested the effect of oxandrolone on indices of organ injury, clinical chemistry parameters and plasma levels of inflammatory mediators. In oxandrolone-treated mice (1mg/kg/day for up to 21 days) there was a significant amelioration of burn-induced accumulation of myeloperoxidase levels in heart and lung (but not the liver and kidney) and significantly lower degree of malon dialdehyde accumulation in the liver (but not the heart, lung and kidney). Oxandrolone-treated mice showed a significant attenuation of the burn-induced elevation in circulating alkaline aminotransferase and amylase levels, while blood urea nitrogen and creatinine levels remained unaffected, indicative of protective effects of the anabolic hormone against burn-induced hepatic and pancreatic (but not renal) functional impairment. Multiple burn-induced inflammatory mediators (TNF-α, IL-1α, IL-1β, IL-4, IL-6, IL-10, IL-12, IP-10, G-CSF, GM-CSF and interferon-γ) were significantly lower in the plasma of oxandrolone-treated animals after burn injury than in the plasma of controls subjected to burns. Finally, oxandrolone significantly accelerated burn wound healing. We conclude that oxandrolone improves organ function, modulates the systemic inflammatory response and accelerates wound healing in a murine model of burn injury.