Severe Organ Dysfunction Research Articles

Acute Kidney Injury in Patients with the Coronavirus Disease 2019: A Multicenter Study

Introduction: Severe acute respiratory viral infections are frequency accompanied by multiple organ dysfunction, including acute kidney injury (AKI). In December 2019, the coronavirus disease 2019 (COVID-19) outbreak began in Wuhan, Hubei Province, China, and rapidly spread worldwide. While diffuse alveolar damage and acute respiratory failure are the main features of COVID-19, other organs may be involved, and the incidence of AKI is not well described. We assessed the incidence and clinical characteristics of AKI in patients with laboratory-confirmed COVID-19 and its effects on clinical outcomes. Methods: We conducted a multicenter, retrospective, observational study of patients with COVID-19 admitted to two general hospitals in Wuhan from 5 January 2020 to 21 March 2020. Demographic data and information on organ dysfunction were collected daily. AKI was defined according to the KDIGO clinical practice guidelines. Early and late AKI were defined as AKI occurring within 72 h after admission or after 72 h, respectively. Results: Of the 116 patients, AKI developed in 21 (18.1%) patients. Among them, early and late AKI were found in 13 (11.2%) and 8 (6.9%) patients, respectively. Compared with patients without AKI, patients with AKI had more severe organ dysfunction, as indicated by a higher level of disease severity status, higher sequential organ failure assessment (SOFA) score on admission, an increased prevalence of shock, and a higher level of respiratory support. Patients with AKI had a higher SOFA score on admission (4.5 ± 2.1 vs. 2.8 ± 1.4, OR 1.498, 95% CI 1.047–2.143 ) and greater hospital mortality (57.1% vs. 12.6%, OR 3.998, 95% CI 1.088–14.613) than patients without AKI in both the univariate and multivariate analyses. Patients with late AKI, but not those with early AKI, had a significantly prolonged length of stay (19.6 vs. 9.6 days, p = 0.015). Conclusion: Our findings show that admission SOFA score was an independent risk factor for AKI in COVID-19 patients, and patients with AKI had higher in-hospital mortality. Moreover, AKI development after 72 h of admission was related to prolonged hospitalization time.

Comparing Mortality Prediction by Quick Sequential Organ Failure Assessment with Emergency Physician Judgment.

The quick sequential organ failure assessment (qSOFA) was proposed to identify infected patients at risk for mortality, an indication of sepsis, in nonintensive care unit settings. This study tests whether qSOFA improves physician prediction of mortality among infected Emergency Department (ED) patients. We performed a secondary analysis of a prospective, observational study of potentially septic ED patients, conducted between two urban, academic medical centers, from July 2016 to December 2017. We enrolled ED patients with two or more systemic inflammatory response syndrome criteria and severe sepsis qualifying organ dysfunction, systolic blood pressure <90 mm Hg, or lactate ≥ 4.0 mmol/L. Infectious etiology was adjudicated retrospectively by paired physician review. We excluded noninfected patients. Treating ED physicians submitted judgment for in-hospital mortality (0%-100%) at hospital admission, and qSOFA was calculated retrospectively using ED data. The primary outcome was in-hospital mortality within 28 days. We used logistic regression to predict mortality using physician judgment, qSOFA, and combined physician judgment and qSOFA. To assess differences between models, 95% confidence intervals for area under the curve (AUC) were derived by bootstrapping with 1,000 iterations. Of 405 patients meeting inclusion criteria, 195 (48.1%) were determined to have infection and analyzed. Of analyzed patients, 16 (8.2%) suffered in-hospital mortality within 28 days. Analyzed patients had a mean age of 58.3 (SD 16.5) years and 78 (40%) were female. qSOFA alone (AUC 0.63; 95% CI: 0.53-0.73) was not superior to unstructured physician judgment (AUC 0.80; 0.70-0.89) when predicting 28-day in-hospital mortality with mean AUC difference 0.17 (0.07-0.28) across bootstrapped datasets. Combining qSOFA with physician judgment (AUC 0.79; 0.69-0.89) did not improve performance compared with physician judgment alone. When predicting 28-day in-hospital mortality among infected ED patients, qSOFA did not outperform or improve physician judgment.

Predicting the clinical trajectory in critically ill patients with sepsis: a cohort study

BackgroundTo develop a mathematical model to estimate daily evolution of disease severity using routinely available parameters in patients admitted to the intensive care unit (ICU).MethodsOver a 3-year period, we prospectively enrolled consecutive adults with sepsis and categorized patients as (1) being at risk for developing (more severe) organ dysfunction, (2) having (potentially still reversible) limited organ failure, or (3) having multiple-organ failure. Daily probabilities for transitions between these disease states, and to death or discharge, during the first 2 weeks in ICU were calculated using a multi-state model that was updated every 2 days using both baseline and time-varying information. The model was validated in independent patients.ResultsWe studied 1371 sepsis admissions in 1251 patients. Upon presentation, 53 (4%) were classed at risk, 1151 (84%) had limited organ failure, and 167 (12%) had multiple-organ failure. Among patients with limited organ failure, 197 (17%) evolved to multiple-organ failure or died and 809 (70%) improved or were discharged alive within 14 days. Among patients with multiple-organ failure, 67 (40%) died and 91 (54%) improved or were discharged. Treatment response could be predicted with reasonable accuracy (c-statistic ranging from 0.55 to 0.81 for individual disease states, and 0.67 overall). Model performance in the validation cohort was similar.ConclusionsThis prediction model that estimates daily evolution of disease severity during sepsis may eventually support clinicians in making better informed treatment decisions and could be used to evaluate prognostic biomarkers or perform in silico modeling of novel sepsis therapies during trial design.Clinical trial registrationClinicalTrials.gov NCT01905033

Transplantation-Associated Microangiopathy (TAM) in Recipients of HLA-Haploidentical Hematopoietic Stem Cell Transplants Using Ptcy, CNI and MMF for GvHD Prophylaxis

Transplant-associated microangiopathy (TAM) is a life-threatening complication after allogeneic transplantation, related to endothelial toxicity caused by chemoradiotherapy, infections, immunosuppressive drugs and GvHD. Clinical manifestations include severe thrombocytopenia, microangiopathic hemolysis and organ dysfunction (e.g. renal, neurological) in the absence of disseminated intravascular coagulation. The reported incidence of TAM after allogeneic hematopoietic stem cell transplantation (HSCT) varies between 0,5 to 70%. Data for TAM occurrence and outcome in the context of HLA-haploidentical transplantation (haplo-HSCT) are rare. Here, we report our experience on TAM incidence, disease manifestation, treatment and outcome in T-cell-replete haplo-HSCT using PTCY as GvHD prophylaxis. We retrospectively analyzed the treatment course of 148 adult patients undergoing haplo-HSCT with regard to the incidence of TAM at our center from January 2012 to April 2019. The diagnosis of TAM required the fulfillment of the criteria as defined by Ruutu et al., Haematologica 2007. Median age of the entire cohort was 54 years (23-74). The majority of patients was transplanted for myeloid disease (60%). Postgrafting immunosuppression consisted of PTCY, CNI and MMF in all patients. Median follow-up time upon survivors was 3 years (4 months - 7 years). Twenty of 148 patients developed TAM, with a cumulative incidence of 10% at day 100. Median interval from haplo-HSCT to TAM onset was 63 days (23-295 days), with seven patients showing TAM after day +100. Median platelet count at diagnosis was 20 x 109/L (range: 6-116), predominantly de novo or worsening thrombocytopenia. Median LDH level was 437 IU/L (305-1445 IU/L). Serum haptoglobin levels were decreased in 85% of the TAM patients. 12/20 patients had active infection at the time of TAM diagnosis, most commonly viral (10/12). All but three patients presented with concurrent active acute GvHD requiring systemic steroid treatment in 16 patients Renal function abnormalities were diagnosed in 55% of the patients affected by TAM, with 4 patients requiring hemodialysis. Nine patients developed grade III hypertension and three patients showed neurologic dysfunction. Upon diagnosis of TAM, CNI dose was reduced (7 patients) or temporarily discontinued (7 patients). No switch to another CNI was performed. FFPs were transfused in nine patients, three patients underwent plasma exchange therapy without any effect. In four patients rituximab was applied. With a CI of 18% vs 2% (p0.002) using a PBSC graft was a risk factor for TAM development when compared to BM. Neither origin of disease (myeloid/lymphoid) nor sex of patient/donor or conditioning intensity (RIC/MAC) influenced the incidence significantly. Estimated one-year and three-year overall survival did not differ between the TAM and the non-TAM cohort (61% vs 61% and 46% vs 47%, p=0.9). Only one patient died because of TAM. With an incidence of 10% at day +100 at our center TAM is a serious but not rare complication after haplo-HSCT using PTCY, CNI and MMF for GvHD prophylaxis. However, in our cohort disease course was moderate with low TAM-associated mortality. The use of a PBSC graft was the only factor influencing TAM incidence. Disclosures Hiddemann: F. Hoffmann-La Roche: Research Funding.

CD19 CAR T-Cell Therapy in Patients with Relapse/Refractory DLBCL: Retrospective Analysis of the Eligibility Criteria

CD19 CAR T-Cell Therapy in Patients with Relapse/Refractory DLBCL: Retrospective Analysis of the Eligibility Criteria

Type 2 myocardial infarction among critically ill elderly patients in the Intensive Care Unit: the clinical features and in-hospital prognosis.

Type 2 myocardial infarction (T2MI) refers to myocardial ischemic necrosis as a result of myocardial oxygen supply/demand mismatch, which are common comorbidities of critically ill patients. The purpose of this study was to investigate the incidence rate and risks of T2MI in critically ill elderly patients and further elucidate in-hospital prognostic factors. A total of 223 critically ill elderly patients admitted to our hospital from October 2016 to September 2018 were recruited. The clinical data and the in-hospital mortality rate were compared between the T2MI and non-T2MI groups. Multivariate linear regression analysis was used to identify independent factors related to T2MI. The clinical data and incidence of T2MI were also compared between patients who survived and those who died; multivariate regression analysis was used to identify independent risk factors for in-hospital death and survival analysis was conducted. In this study, the incidence of T2MI was 24.2% (54/223), and the mortality rate of critically ill elderly patients was 39.0% (87/223). Multivariate linear regression analysis showed that severe hypoxemia, arrhythmia, shock, and multiple organ dysfunction syndrome (MODS) were independent risk factors of T2MI. Compared to the survival patients, the use of mechanical ventilation, the incidence of T2MI, APACHE II score, troponin T, high-sensitivity C-reactive protein, and procalcitonin levels were significantly higher in patients who died, while the estimated glomerular filtration rate (eGFR) was significantly decreased (all P < 0.05). In-hospital mortality was significantly increased in patients with T2MI (59.3% vs. 32.5%, P < 0.001). After adjustment for relevant factors, the incidence of T2MI, mechanical ventilation required, and eGFR reduction were independent and significant predictors of in-hospital death. Critically, ill elderly patients have a high incidence of T2MI. In addition to severe hypoxia, shock, and arrhythmia, MODS is also associated with T2MI. At the same time, the risk of in-hospital death is increased in patients with type 2 MI.

In-Hospital Post-Operative Infection after Heart Transplantation: Epidemiology, Clinical Management, and Outcome.

Background: Infection is a major cause of morbidity and mortality after heart transplantation (HT). Little information about its importance in the immediate post-operative period is available. The aim of this study was to analyze the characteristics, incidence, and outcomes of in-hospital post-operative infections after HT. Methods: We conducted an observational, single-center study based on 677 adults who underwent HT from 1991 to 2015 and who survived the surgical intervention. In-hospital post-operative infections were identified retrospectively according to the medical finding in the clinical records. Results: Over a mean hospital stay of 24.5 days, 239 patients (35.3%) developed 348 episodes of infection (2 episodes per 100 patient-days). The most common sources of infection were those related to invasive procedures (respiratory infections, 115 [33%]; urinary tract infections, 47 [13.5%]; bacteremia, 42 [12.1%]; surgical site infections, 25 [7.2%]), in addition to abdominal focus (33, 9.5%). Enterobacteriaceae (76, 21.8%) and gram-positive cocci (58, 16.7%) were the predominant germs, although opportunistic infections were not infrequent (69, 19.8%). Ninety-five septic episodes were detected with a mean Sequential Organ Failure Assessment Score of 9.5 ± 5.3 points, with hemodynamic failure being the most severe organ dysfunction and renal dysfunction the most frequent one. Management included broad-spectrum antibiotics in 48.8% of episodes and surgical management in 13.8%. The overall antimicrobial success rate was 96.3%. Higher in-hospital mortality was observed among infected patients (15.1% vs. 10.3%), but this difference was not statistically significant (p = 0.067). The one-year survival and events were not different between patients suffering from a post-operative infection and those who did not. Conclusions: In-hospital infections were frequent in the post-operative period after HT and were associated with a poor short-term outcome. Patients who survived sepsis had a similar one-year morbidity and mortality compared with patients who did not develop an infection.

Home Parenteral Nutrition Prolongs Survival in Incurable Malnourished Cancer Patients: A Prospective Cohort Study

Background: Guidelines recommend home parenteral nutrition (HPN) if incurable cancer patients are unable to meet their nutritional requirements by oral/enteral route and are at risk of death due to malnutrition. However, the evidence base is lacking and recommendation has been the result of expert consensus. The aim of this study was the comparison of incurable malnourished cancer patients who received HPN with a similar group of patients, equally eligible for HPN, who did not receive HPN for logistic reasons or refusal by the patient. Methods: In this prospective longitudinal cohort study, patients were assessed for HPN eligibility following the European guidelines. In the eligible population, those who received both HPN and chemotherapy were excluded, those receiving only HPN were included as the study group (HPN+ group) while who received neither HPN nor chemotherapy but only artificial hydration were included as the control group (HPN- group). The primary outcome was overall survival. Findings: Between October 1, 2012, and September 30, 2015, 301 patients were assessed for HPN eligibility and 86 patients (28·6%) were excluded for having severe organ dysfunction or Karnofsky Performance Status <50. In outcome analysis, 90 patients (29·9%) were excluded for receiving both HPN and chemotherapy while 125 (41·5%) were included, 89 in HPN+ group (29·5%) and 36 in HPN- group (12%). The survival of the two groups showed a significant difference favouring patients on HPN (median overall survival: 4·3 vs 1·5 months, p<0·001); HR 0·028 [95% CI 0·015-0·059]). The multivariate analysis of the risk factors for mortality showed that not receiving HPN accounted for the strongest one (HR 25·72 [95% CI 13·65-48·44]). Interpretation: Survival of incurable malnourished cancer patients is significantly correlated with HPN administration which produces a threefold survival increase. These data support the recommendation that HPN should be considered to prolong survival in these patients. Funding Statement: Regional Public Healthcare Office (Piedmont Region, Italy). Declaration of Interests: PC reports grants from the Regional Public Healthcare Office (Piedmont Region, Italy). PC reports honoraria for speaking and teaching from Baxter. The other authors declare that they have no competing interests. Ethics Approval Statement: Ethics Committee approval was obtained and written informed consent was obtained from each patient prior to any procedures. The consent to participate was obtained from the chief investigator (PC). The study was conducted in compliance with the Institutional Review Board/Human Subjects Research Committee requirements.

3240 Cytomegalovirus Gastritis in an Immunocompetent Patient

INTRODUCTION: Cytomegalovirus (CMV) is a large enveloped virus of the Herpes virus family. CMV frequently infects humans and can establish latent infection after an acute infection. In immune-compromised patients, CMV can have neurological, cutaneous, gastrointestinal (GI), cardiac or ocular manifestations and can cause severe organ dysfunction leading to significant morbidity and mortality. The colon and the stomach are the common sites of GI infection. CASE DESCRIPTION/METHODS: 54 year old female with no prior medical history presented to the hospital with complaints of shortness of breath for the last 3 days and was noted to be in rapid atrial fibrillation. Patient was admitted and subsequently found to have severe mitral valve stenosis and moderate to severe tricuspid regurgitation. The patient was seen by Cardio-thoracic surgery and underwent mitral valve replacement and tricuspid ring annuloplasty. During the post-operative period, the patient was found to have blood in her stool and was evaluated by the gastroenterology service. In evaluating her GI bleed, she underwent an upper endoscopy. Findings on upper endoscopy included, small hiatus hernia and a single small ulcer in the incisura of the stomach. An area of gastritis was found in the antrum/body of the stomach. The mucosa appeared nodular and edematous. Biopsies were taken from the antrum and showed gastric antral type mucosa with reactive gastropathy. CMV viral inclusions were present in the gastric pit epithelial cells, confirmed on immunostain for CMV. HIV and quantiferon gold tests were negative and the patient was not known to be on any immunosuppressive therapies. Serum CMV DNA PCR was tested on 2 subsequent days which showed 4858 IU/ml and 5548 IU/mL respectively. DISCUSSION: CMV infection of the GI tract is a common manifestation of CMV disease in the immunocompromised patients such as Acquired immunodeficiency syndrome, organ/ bone marrow transplantation and other condition requiring chronic immunosuppressive therapy. CMV of the GI tract is rare in an immunocompetent patient and only few cases have been reported so far. Presenting symptoms include odynophagia/dysphagia, epigastric pain, nausea/vomiting, GI bleeding. However, in up to 7% of cases it can be asymptomatic. Endoscopic features of CMV infection include macroscopic normal mucosa, diffuse erythema, nodules, pseudotumors, erosions and ulcers. Detection of intranuclear inclusions, also known as “owl's eye,” is the hallmark of CMV infection.

Application of imatinib plasma concentration monitoring in the whole process management of gastrointestinal stromal tumor patients

Objective: To investigate the significance of monitoring imatinib mesylate (IM) plasma concentrations in patients with gastrointestinal stromal tumor (GIST). Methods: A retrospective descriptive study was carried out. Inclusion criteria: (1) patients with GIST confirmed by postoperative pathology or puncture pathology receiving maintenance therapy of IM; (2) administration of same dose of IM for at least 4 weeks (achieving steady - state plasma concentration). Patients who had severe organ dysfunction, received IM generics, or received IM simultaneously with other drugs significantly affecting IM pharmacokinetic were excluded. A total of 185 patients at the GIST Clinic of Renji Hospital, Shanghai Jiaotong University School of Medicine from August 2018 to May 2019 were enrolled, including 114 males (61.6%) and 71 females (38.4%) with a median age of 60 years old (range, 30-89 years), and 63 advanced cases. Patients receiving preoperative or postoperative adjuvant therapy were given IM 400 mg QD; patients with KIT exon 9 mutation or with disease progression during IM 400 mg QD treatment were given IM 600 mg QD. If the patient had adverse reactions such as myelosuppression during the medication, IM would be reduced or given BID per day. The peripheral venous blood was collected (22 to 24 hours after the last dose for patients who took IM QD and 2 hours before the first dose per day for those who took IM BID). IM plasma concentration was measured through high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). Correlation analysis between IM plasma concentration results and clinical data was performed using linear regression analysis. Results: A total of 241 stable blood samples of IM plasma concentration from 185 patients were finally collected. The IM plasma concentrations were significantly different between the doses of 300 mg/d and 400 mg/d [(942.4±433.5) μg/L vs. (1340.0±500.1) μg/L, t=6.317, P<0.001], and between 400 mg/d and 600 mg/d [(1340.0±500.1) μg/L vs. (2188.0±875.5) μg/L, t=3.557, P=0.004]. Among the blood samples of 57 patients receiving IM 300 mg/d, the IM plasma concentration of the advanced patients was significantly lower than that of the non-advanced patients [(795.6±225.8) μg/L vs. (992.2±484.4) μg/L, t=2.088, P=0.042]. Among the 137 blood samples of patients receiving IM 400 mg/d, the IM plasma concentration was higher in patients aged >60 years than those aged ≤60 years [(1461.0±595.3) μg/L vs. (1240.0±380.9) μg/L, t=2.528, P=0.013] and the IM plasma concentration of cases with diarrhea was significantly lower than that of those without diarrhea [(745.8±249.6) μg/L vs. (1382.0±486.9) μg/L, t=6.794, P<0.001]. Gender, primary location, surgical procedure, mutated gene, mutation type, or time of administration was associated with IM plasma concentration no matter in patients taking IM doses of 400 mg/d or 300 mg/d (all P>0.05). Regression analysis showed that body mass (P=0.004 and P=0.019), body mass index (P=0.016 and P=0.042), and body surface area (P=0.007 and P=0.028) were all negatively correlated with IM plasma concentrations in patients taking IM doses of 300 mg/d and 400 mg/d. Within the 137 patients who received a fixed oral dose of 400 mg/d IM, 17 patients received oral 200 mg BID, whose IM plasma drug concentration was not significantly different compared with that of 120 patients who received 400 mg IM QD [(1488.0±408.3) μg/L vs. (1319.0±509.7) μg/L, t=1.307, P=0.193]. Conclusions: Monitoring IM plasma concentration is significant throughout the whole process of management of GIST patients receiving IM treatment. In particular, regular monitoring IM plasma concentration and developing appropriate treatment strategies can bring better therapeutic benefits for patients with low doses, diarrhea, advanced condition and older age.

Impact of intensive care unit supportive care on the physiology of Ebola virus disease in a universally lethal non-human primate model

BackgroundThere are currently limited data for the use of specific antiviral therapies for the treatment of Ebola virus disease (EVD). While there is anecdotal evidence that supportive care may be effective, there is a paucity of direct experimental data to demonstrate a role for supportive care in EVD. We studied the impact of ICU-level supportive care interventions including fluid resuscitation, vasoactive medications, blood transfusion, hydrocortisone, and ventilator support on the pathophysiology of EVD in rhesus macaques infected with a universally lethal dose of Ebola virus strain Makona C07.MethodsFour NHPs were infected with a universally lethal dose Ebola virus strain Makona, in accordance with the gold standard lethal Ebola NHP challenge model. Following infection, the following therapeutic interventions were employed: continuous bedside supportive care, ventilator support, judicious fluid resuscitation, vasoactive medications, blood transfusion, and hydrocortisone as needed to treat cardiovascular compromise. A range of physiological parameters were continuously monitored to gage any response to the interventions.ResultsAll four NHPs developed EVD and demonstrated a similar clinical course. All animals reached a terminal endpoint, which occurred at an average time of 166.5 ± 14.8 h post-infection. Fluid administration may have temporarily blunted a rise in lactate, but the effect was short lived. Vasoactive medications resulted in short-lived improvements in mean arterial pressure. Blood transfusion and hydrocortisone did not appear to have a significant positive impact on the course of the disease.ConclusionsThe model employed for this study is reflective of an intramuscular infection in humans (e.g., needle stick) and is highly lethal to NHPs. Using this model, we found that the animals developed progressive severe organ dysfunction and profound shock preceding death. While the overall impact of supportive care on the observed pathophysiology was limited, we did observe some time-dependent positive responses. Since this model is highly lethal, it does not reflect the full spectrum of human EVD. Our findings support the need for continued development of animal models that replicate the spectrum of human disease as well as ongoing development of anti-Ebola therapies to complement supportive care.

Elevated ferritin and soluble CD25 in critically ill patients are associated with parameters of (hyper) inflammation and lymphocyte cytotoxicity.

Critically ill patients may develop a potentially fatal hyperinflammatory condition known as secondary (acquired) hemophagocytic lymphohistiocytosis (sHLH), the cause of which is unclear. We evaluated serum ferritin and soluble CD25 (sCD25) in critically ill patients, and their association with other parameters of inflammation and critical illness. Moreover, aiming to better understand the pathogenesis of sHLH, we also evaluated lymphocyte cytotoxicity parameters and correlations with the inflammatory markers ferritin and sCD25. In a prospective observational study, 32 patients with ferritin ≥500 µg/L (24 with sepsis) were studied on admission to an intensive care unit (ICU) with regard to ferritin and corresponding clinical and laboratory features including sCD25, and detailed lymphocyte cytotoxicity and genetic analyses whenever possible. Critically ill patients had elevated, positively correlated levels of serum ferritin and sCD25 (rs=0.465, P=0.008); both associated with other risk factors of poor outcome in critically ill, such as thrombocytopenia (rs=-0.534, P=0.002 and rs=-0.421, P=0.018, respectively), and sCD25 with hypoalbuminemia (rs=-0.678, P<0.001) and life support treatments (rs=0.479, P=0.006). Interestingly, ferritin levels were inversely associated with natural killer (NK)-cell cytotoxicity (rs=-0.462, P=0.047) and degranulation (rs=-0.504, P=0.030). Moreover, of four patients with abnormally low cytotoxicity, three (75%) had <5% circulating NK-cells. Our study suggests that hyperferritinemia and sCD25 correlate with other laboratory parameters indicative of severe hyperinflammation and organ dysfunction in critically ill ICU-patients, indicating their value in identifying hyperinflammatory critically ill patients for early intervention. Furthermore, it suggests that hyperferritinemia and hyperinflammation may partly be associated with a low percentage circulating NK-cells, and hence, the associated low lymphocyte cytotoxicity.

Current Epidemiology of Surgical Sepsis

We sought to compare traditional inpatient outcomes to long-term functional outcomes and mortality of surgical intensive care unit (SICU) patients with sepsis. As inpatient sepsis mortality declines, an increasing number of initial sepsis survivors now progress into a state of chronic critical illness (CCI) and their post-discharge outcomes are unclear. We performed a prospective, longitudinal cohort study of SICU patients with sepsis. Among this recent cohort of 301 septic SICU patients, 30-day mortality was 9.6%. Only 13 (4%) patients died within 14 days, primarily of refractory multiple organ failure (62%). The majority (n = 189, 63%) exhibited a rapid recovery (RAP), whereas 99 (33%) developed CCI. CCI patients were older, with greater comorbidities, and more severe and persistent organ dysfunction than RAP patients (all P < 0.01). At 12 months, overall cohort performance status was persistently worse than presepsis baseline (WHO/Zubrod score 1.4 ± 0.08 vs 2.2 ± 0.23, P > 0.0001) and mortality was 20.9%. Of note at 12 months, the CCI cohort had persistent severely impaired performance status and a much higher mortality (41.4%) than those with RAP (4.8%) after controlling for age and comorbidity burden (Cox hazard ratio 1.27; 95% confidence interval, 1.14-1.41, P < 0.0001). Among CCI patients, independent risk factors for death by 12 months included severity of comorbidities and persistent organ dysfunction (sequential organ failure assessment ≥6) at day 14 after sepsis onset. There is discordance between low inpatient mortality and poor long-term outcomes after surgical sepsis, especially among older adults, increasing comorbidity burden and patients that develop CCI. This represents important information when discussing expected outcomes of surgical patients who experience a complicated clinical course owing to sepsis.

Circulating dipeptidyl peptidase 3 is a myocardial depressant factor: dipeptidyl peptidase 3 inhibition rapidly and sustainably improves haemodynamics

Acute heart failure is a high mortality disease and its pathophysiology is not completely understood. Dipeptidyl peptidase 3 (DPP3) is a cytosolic enzyme involved in angiotensin II and enkephalins cleavage. The aim of this study was to investigate the association of circulating DPP3 (cDPP3) levels and mortality in cardiogenic shock patients and to determine the effects of high cDPP3 on organ function in a heart failure (HF) model in mice. cDPP3 was measured in 174 patients in cardiogenic shock and high cDPP3 levels were associated with an increased short-term mortality risk (standardized hazard ratio: 1.4 (1.1-1.8)) and severe organ dysfunction. Additionally, a rapid decrease in cDPP3 in cardiogenic shock patients within 24 h of admission was associated with a favourable outcome. This study showed that injection of DPP3 induced myocardial depression (-10 ± 2% of shortening fraction) and impaired kidney haemodynamics (+0.30 ± 0.02 of renal resistive index) in healthy mice. cDPP3 inhibition by Procizumab, a specific antibody directed against cDPP3, promptly normalized cardiac function and kidney haemodynamics in an acute heart failure mouse model, with a marked reduction in oxidative stress and inflammatory signalling. Our study demonstrated cDPP3 is a newly discovered myocardial depressant factor, the levels of which at admission are associated with mortality in severe HF patients. Furthermore, inhibition of cDPP3 by Procizumab improved haemodynamics in a mouse model of HF. Our results suggest that DPP3 could be a new biomarker and biotarget for severe HF.

Levosimendan in septic shock in patients with biochemical evidence of cardiac dysfunction: a subgroup analysis of the LeoPARDS randomised trial

Myocardial dysfunction is common in sepsis but optimal treatment strategies are unclear. The inodilator, levosimendan was suggested as a possible therapy; however, the levosimendan to prevent acute organ dysfunction in Sepsis (LeoPARDS) trial found it to have no benefit in reducing organ dysfunction in septic shock. In this study we evaluated the effects of levosimendan in patients with and without biochemical cardiac dysfunction and examined its non-inotropic effects. Two cardiac biomarkers, troponin I (cTnI) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and five inflammatory mediators were measured in plasma from patients recruited to the LeoPARDS trial at baseline and over the first 6days. Mean total Sequential Organ Failure Assessment (SOFA) score and 28-day mortality were compared between patients with normal and raised cTnI and NT-proBNP values, and between patients above and below median values. Levosimendan produced no benefit in SOFA score or 28-day mortality in patients with cardiac dysfunction. There was a statistically significant treatment by subgroup interaction (p = 0.04) in patients with NT-proBNP above or below the median value. Those with NT-proBNP values above the median receiving levosimendan had higher SOFA scores than those receiving placebo (mean daily total SOFA score 7.64 (4.41) vs 6.09 (3.88), mean difference 1.55, 95% CI 0.43-2.68). Levosimendan had no effect on the rate of decline of inflammatory biomarkers. Adding levosimendan to standard care in septic shock was not associated with less severe organ dysfunction nor lower mortality in patients with biochemical evidence of cardiac dysfunction.

Abstract 448: Predicting Blood Pressure Response to Fluid Bolus Therapy Using Neural Networks with Clinical Interpretability

Background: Fluid bolus therapy (FBT), the rapid infusion of fluid, has been recommended as the primary-line treatment for acute hypotensive episode (AHE) that occurs in about 41% of patients in ICU. However, previous studies have reported that approximately one-third of the acute hypotensive patients do not successfully respond to FBT treatment. Avoiding the administration of FBT that will not successfully resolve AHE might prevent an inappropriate increase of the total fluid volume administered to ICU patients, potentially reducing their risk for severe organ dysfunction and increased mortality. Methods: Our study utilized regression models and attention-based recurrent neural network (RNN) algorithms and two large-scale information system databases, the multi-clinical MIMIC-ICU one and the multi-center Philips eICU CRD one, to predict the successful response to FBT among hypotensive patients in ICUs. We investigated both time-aggregated modeling and time-series modeling using RNN with the attention mechanism (AM) for clinical interpretability. The successful FBT is defined by intensive care experts as the presence of the maximum mean atrial pressure (MAP) &gt; 1.15 * average (MAP) at least once, where maximum(MAP) is the maximal MAP from the FBT starting time to two hours after FBT, and average (MAP) is the average MAP from 30 minutes before FBT until 10 minutes after FBT. Results: The stacked RNN with AM yielded the highest accuracy of 0.852 and area under the curve (AUC) value of 0.925 when trained and tested on the MIMIC-ICU dataset. The top features learned from regression include the patient's respiratory rate, diastolic pressure, temperature, and bicarbonate and base excess levels in blood. Preliminary results from training and testing the RNN on the Philips eICU-CRD database yielded an accuracy of 0.812 and AUC value of 0.769. We were also able to identify timesteps close to the time of FBT administration as clinically meaningful using the RNN models with AM. Conclusion: This is the first study that utilizes machine learning for identifying hypotensive patients in ICUs who will have sufficient blood pressure recovery after FBT. Utilizing AM and identifying the top features learned also provided clinical interpretability to the models we used.

Association of Organ Dysfunction Scores and Functional Outcomes Following Pediatric Critical Illness.

Short-term and long-term morbidity and mortality are common following pediatric critical illness. Severe organ dysfunction is associated with significant in-hospital mortality in critically ill children; however, the performance of pediatric organ dysfunction scores as predictors of functional outcomes after critical illness has not been previously assessed. Secondary analysis of a prospective observational cohort. A multidisciplinary, tertiary, academic PICU. Patients less than or equal to 18 years old admitted between June 2012 and August 2012. None. The maximum pediatric Sequential Organ Failure Assessment and Pediatric Logistic Organ Dysfunction-2 scores during admission were calculated. The Functional Status Scale score was obtained at baseline, 6 months and 3 years following discharge. New morbidity was defined as a change in Functional Status Scale greater than or equal to 3 points from baseline. The performance of organ dysfunction scores at discriminating new morbidity or mortality at 6 months and 3 years was measured using the area under the curve. Seventy-three patients met inclusion criteria. Fourteen percent had new morbidity or mortality at 6 months and 23% at 3 years. The performance of the maximum pediatric Sequential Organ Failure Assessment and Pediatric Logistic Organ Dysfunction-2 scores at discriminating new morbidity or mortality was excellent at 6 months (areas under the curves 0.9 and 0.88, respectively) and good at 3 years (0.82 and 0.79, respectively). Severity of organ dysfunction is associated with longitudinal change in functional status and short-term and long-term development of new morbidity and mortality. Maximum pediatric Sequential Organ Failure Assessment and Pediatric Logistic Organ Dysfunction-2 scores during critical illness have good to excellent performance at predicting new morbidity or mortality up to 3 years after critical illness. Use of these pediatric organ dysfunction scores may be helpful for prognostication of longitudinal functional outcomes in critically ill children.

Genetics of Malaria Inflammatory Responses: A Pathogenesis Perspective.

Despite significant progress in combating malaria in recent years the burden of severe disease and death due to Plasmodium infections remains a global public health concern. Only a fraction of infected people develops severe clinical syndromes motivating a longstanding search for genetic determinants of malaria severity. Strong genetic effects have been repeatedly ascribed to mutations and allelic variants of proteins expressed in red blood cells but the role of inflammatory response genes in disease pathogenesis has been difficult to discern. We revisited genetic evidence provided by inflammatory response genes that have been repeatedly associated to malaria, namely TNF, NOS2, IFNAR1, HMOX1, TLRs, CD36, and CD40LG. This highlighted specific genetic variants having opposing roles in the development of distinct malaria clinical outcomes and unveiled diverse levels of genetic heterogeneity that shaped the complex association landscape of inflammatory response genes with malaria. However, scrutinizing genetic effects of individual variants corroborates a pathogenesis model where pro-inflammatory genetic variants acting in early infection stages contribute to resolve infection but at later stages confer increased vulnerability to severe organ dysfunction driven by tissue inflammation. Human genetics studies are an invaluable tool to find genes and molecular pathways involved in the inflammatory response to malaria but their precise roles in disease pathogenesis are still unexploited. Genome editing in malaria experimental models and novel genotyping-by-sequencing techniques are promising approaches to delineate the relevance of inflammatory response gene variants in the natural history of infection thereby will offer new rational angles on adjuvant therapeutics for prevention and clinical management of severe malaria.

Severe Dengue and Associated Hemophagocytic Lymphohistiocytosis in PICU.

To study the clinico-laboratory profile and outcome of children with severe dengue and dengue-associated hemophagocytic lymphohistiocytosis (HLH). In this retrospective study, 22 children with laboratory confirmed severe dengue admitted to pediatric intensive care unit (PICU) were enrolled. Clinical features, laboratory parameters, and outcome were noted and compared between cases fulfilling HLH-2004 criteria and those without HLH. Median (IQR) age was 8 (5-10.3) y. Fever was present for mean (SD) duration of 5.3 (2.1) d. Vomiting, respiratory distress, pain abdomen and hepatomegaly were other clinical features. Thrombocytopenia, anemia and elevated serum transaminases were noted in 91%, 41% and 30% respectively; coagulopathy and hypoalbuminemia were seen in 36% each. Half (n = 11, 50%) had dengue shock syndrome. Acute respiratory distress syndrome (ARDS) (n = 7, 32%) and acute kidney injury (AKI) (n = 6, 28%) were other major organ dysfunctions. Mean (SD) duration of PICU stay was 3.6 (1.5) d with 13.6% mortality. HLH was noted in 7 (32%) cases at a median (IQR) hospital stay of 5 (2-8) d. Children with HLH had significantly higher Pediatric Index of Mortality 2 (PIM 2) score at admission and higher frequency of pain abdomen, anemia, hypoalbuminemia, elevated alanine aminotransferase (ALT) and ARDS. Length of PICU stay (5.1 vs. 2.9 d) and mortality (28.6% vs. 6.7%) were higher in HLH group, however the difference was not statistically significant. Steroids were used in 4 cases with HLH and all survived, whereas among 3 who did not receive steroids, 2 died (p = 0.23). Severe dengue presents with life-threatening organ dysfunctions. HLH is increasingly recognized in dengue infection and maybe considered as a differential diagnosis in children with lower hemoglobin, hypoalbuminemia, elevated ALT and severe organ dysfunction.

Clinical profile and short-term outcomes in neonates with septic shock

Background: Neonatal sepsis is a syndrome causing severe organ dysfunction triggered by a dysregulated host in response to an infection, affecting millions of neonates. In such situations, early identification and management in the initial hours dramatically improves the outcome. Hence, it was taken up to study the incidence, clinical profile and short-term outcomes of neonates with septic shock.Methods: Hospital based prospective observational study on 95 neonates admitted to neonatal intensive care unit in the department of Paediatrics at Acharya Vinobha Bhave rural hospital, Sawangi, Wardha from 1st August 2016 to 31st July 2018.Neonates diagnosed with septic refractory shock were enrolled after taking IEC approval and assent form and those with non-septic aetiology shock were excluded. Statistical analysis was done to establish correlation between neonatal variables and outcome.Results: 95 neonates fulfilled the inclusion criteria and were recruited. Out of these, 37 and 53 were outborn and inborn respectively. Maximum neonates were preterm and males. Neonates with birth weight 1000-1499 grams to those less than 1000 was 4.2:1. Normal vaginal delivery was more common as compared to lower segment caesarean section (LSCS). Blood culture positivity was in 44.2%. Age of presentation with shock ranged from 1 to 20 days and duration of shock ranged from 2 hours to 192 hours. Most infants were ventilated (84%) and it was more among those who died.Conclusions: Septic shock is the most common type, carrying high morbidity and mortality (more than 60%). Laboratory and clinical parameters (TLC, Platelet count, CRP, Blood culture, duration of shock, HR, RR, BP or arterial blood gas) (p&gt;0.05) did not carry a prognostic value in predicting the outcome of such neonates. Early identification and intervention remains the key in managing such a challenging neonatal condition.