Faculty Bibliography

Introduction. IV fluid treatment is a central component of septic shock resuscitation but in excess is associated with adverse effects. Dynamic measurement of stroke volume (SV) following a passive leg raise (PLR) is a safe and feasible method of rapidly predicting the effectiveness of fluid-induced augmentation of cardiac output. The FRESH study demonstrated that SV-guided dynamic assessment could alter the amount of IV fluid administered to patients with septic shock and improve patient outcomes.1 Additionally, the kidney is known to be vulnerable to injury during septic shock. The goal of this analysis was to evaluate the incidence of AKI in the FRESH patient population. Methods. FRESH was a prospective, randomized global clinical trial in adults with septic shock comparing PLR-guided SV responsiveness (intervention) as a guide for fluid management versus usual care.1 Patients presented to the ER with sepsis associated hypotension and anticipated ICU admission. In the Intervention arm, patients were assessed for fluid responsiveness before any clinically driven fluid bolus or increase in vasopressors. If a patient's stroke volume increased by >= 10% in response to a PLR, they were considered fluid responsive and fluid was recommended as the first therapy. If a patient's stroke volume increased by < 10% then they were considered not to be fluid responsive and vasopressors were recommended as the first therapy. The protocol included reassessment and therapy as indicated by the PLR result. Results. 83 patients were randomized to the Intervention arm and 41 patients to the Usual Care control arm. Patients in the treatment arm received less fluid over the 72 h treatment period (3354.2 +/- 2179.6) compared to the control group (4721.3 +/- 3319.1, p = 0.007). Patients in the treatment arm displayed a statistically significant decrease in the need for kidney replacement therapy (5.1% vs 17.5%, p = 0.04)0.1 An analysis of patient baseline and pre hospitalization creatinine levels over the course of hospitalization indicated that in addition to a decrease in the need for KRT, patients in the treatment arm exhibited a decrease in observed AKI status. In the treatment arm 25.9% of patients exhibited a twofold increase in creatinine over their true baseline creatinine value (KDIGO stage 2), compared to 48% of patients in the control arm (p = 0.04). Conclusion. Physiologically-informed fluid and vasopressor resuscitation using PLR-induced SV change to guide personalized management of septic shock was associated with a lower requirement of administered fluid and a decreased need for KRT. An analysis of creatinine levels indicated a potential benefit to preserving kidney function and decreasing the rate of AKI. Administering fluid only when it is effective at improving perfusion (SV change > 10%) may help preserve kidney function and importantly limit the deleterious effect of volume overload on renal function

BACKGROUND:Estimates for dead space ventilation have been shown to be independently associated with an increased risk of mortality in the acute respiratory distress syndrome and small case series of COVID-19-related ARDS. METHODS:Secondary analysis from the PRoVENT-COVID study. The PRoVENT-COVID is a national, multicenter, retrospective observational study done at 22 intensive care units in the Netherlands. Consecutive patients aged at least 18 years were eligible for participation if they had received invasive ventilation for COVID-19 at a participating ICU during the first month of the national outbreak in the Netherlands. The aim was to quantify the dynamics and determine the prognostic value of surrogate markers of wasted ventilation in patients with COVID-19-related ARDS. RESULTS:ratio. After adjustment for a base risk model that included chronic comorbidities and ventilation- and oxygenation-parameters, none of the dead space estimates measured at the start of ventilation or the following days were significantly associated with 28-day mortality. CONCLUSIONS:There is significant impairment of ventilation in the early course of COVID-19-related ARDS but quantification of this impairment does not add prognostic information when added to a baseline risk model. TRIAL REGISTRATION:ISRCTN04346342. Registered 15 April 2020. Retrospectively registered.

The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro, and in vivo analyses, we report that topoisomerase 1 (TOP1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of topotecan (TPT), an FDA-approved TOP1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as 4 days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of TOP1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing TOP1 inhibitors for severe coronavirus disease 2019 (COVID-19) in humans.

INTRODUCTION Surrogates for impaired ventilation such as estimated dead-space fractions and the ventilatory ratio are independently associated with an increased risk of mortality in the acute respiratory distress syndrome (ARDS) and small case series of COVID-19 related ARDS. METHODS This study aimed to quantify the dynamics and determine the prognostic value of surrogate markers of impaired ventilation in patients with COVID-19 related ARDS. The present study is a secondary analysis of the PRactice Of VENTilation in COVID-19 patients (PROVENT-COVID) in 22 intensive care unit hospitals in the Netherlands. Surrogates of impaired ventilation such as the estimated dead space fraction (by Harris-Benedict-VD/VT HB and direct method-VD/VT DIR), ventilatory ratio (VR), and end-tidal-to-arterial PCO2 ratio (PETCO2/PaCO2) were used. RESULTS 927 consecutive patients admitted with COVID-19 related ARDS were included in this study. Surrogates of impaired ventilation were significantly higher in non-survivors than survivors at baseline and during the following days of mechanical ventilation (p <0.001). As ARDS severity increased, mortality increased with successive tertiles for VD/VT HB and VD/VT DIR, and VR, and decreased with successive tertiles for PETCO2/PaCO2. Mortality over the first 28 days was higher in patients in the high group of dead space fraction by VD/VT HB (16.4% vs. 12.3%; p = 0.003), but similar in the groups considering the dead space fraction by VD/VT DIR (15.4% vs. 13.3%; p = 0.100), and VR (15.5% vs. 13.2%; p = 0.080) (Figure 2). After adjustment for a base risk model that included chronic comorbidities, ventilation and oxygenation parameters, none of the surrogates of impaired ventilation measured at the start of ventilation or the following days were significantly associated with 28-day mortality. CONCLUSION Surrogate markers for impaired ventilation are abnormal at the start of invasive ventilation in patients with COVID-19 related ARDS and worsen during consequent days. Ventilation impairment seems to be more extensive in non-survivors than in survivors, but they do not yield prognostic information when added to a baseline risk model. In the absence of bedside capnography, surrogates of impaired ventilation may serve as an important tool to assess the severity of COVID-19 related ARDS along with other variables such as oxygenation abnormalities and respiratory mechanics

Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal ( Mycoplasma salivarium ), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized.

The ongoing pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro and in vivo analyses, we report that Topoisomerase 1 (Top1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of Topotecan (TPT), a FDA-approved Top1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as four days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of Top1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing Top1 inhibitors for COVID-19 in humans.

BACKGROUND/UNASSIGNED:Little is known about hypoxemia surrounding endotracheal intubation in the critically ill. Thus, we sought to identify risk factors associated with peri-intubation hypoxemia and its effects' on the critically ill. METHODS/UNASSIGNED:Data from a multicenter, prospective, cohort study enrolling 1,033 critically ill adults who underwent endotracheal intubation across 16 medical/surgical ICUs in the United States from July 2015-January 2017 were used to identify risk factors associated with peri-intubation hypoxemia and its effects on patient outcomes. We defined hypoxemia as any pulse oximetry ≤ 88% during and up to 30 minutes following endotracheal intubation. RESULTS/UNASSIGNED:. CONCLUSIONS/UNASSIGNED:Patients with pre-existing noninvasive ventilation and volume loading who were intubated emergently in the setting of hemodynamic compromise with bag-mask ventilation described as moderate-severe were at increased risk for peri-intubation hypoxemia. Higher baseline oxygenation was found to be protective against peri-intubation hypoxemia. Peri-intubation hypoxemia was associated with in-hospital mortality but not ICU length of stay. TRIAL REGISTRATION/UNASSIGNED:Clinicaltrials.gov identifier: NCT02508948 and Registered Report Identifier: RR2-10.2196/11101.

BACKGROUND:Fluid and vasopressor management in septic shock remains controversial. In this randomized controlled trial, we evaluated the efficacy of dynamic measures (stroke volume change during passive leg raise) to guide resuscitation and improve patient outcome. RESEARCH QUESTION/OBJECTIVE:Will resuscitation guided by dynamic assessments of fluid responsiveness in patients with septic shock improve patient outcomes? STUDY DESIGN/METHODS:and Methods: Prospective, multicenter, randomized clinical trial at 13 hospitals in the United States and United Kingdom. Patients presented to Emergency Rooms with sepsis associated hypotension and anticipated Intensive Care Unit (ICU) admission. Intervention arm patients were assessed for fluid responsiveness before clinically driven fluid bolus or increase in vasopressors. The protocol included reassessment and therapy as indicated by the PLR result. The control arm received Usual Care. Primary clinical outcome was positive fluid balance at 72 hours or ICU discharge, whichever occurred first. RESULTS:In modified-ITT (mITT) analysis including 83 Intervention and 41 Usual Care eligible patients, fluid balance at 72 hours or ICU discharge was significantly lower (-1.37L favoring Intervention arm, 0.65 ± 2.85L Intervention arm vs. 2.02 ± 3.44L Usual Care arm, p=0.021. Fewer patients required renal replacement therapy (5.1% vs 17.5%, p=0.04) or mechanical ventilation (17.7% vs 34.1%, p=0.04) in the Intervention arm compared to Usual Care. In the all-randomized Intent to Treat (ITT) population (102 Intervention, 48 Usual Care) there were no significant differences in safety signals. INTERPRETATION/CONCLUSIONS:Physiologically informed fluid and vasopressor resuscitation using passive leg raise-induced stroke volume change to guide management of septic shock is safe and demonstrated lower net fluid balance and reductions in the risk of renal and respiratory failure. Dynamic assessments to guide fluid administration may improve outcomes for septic shock patients compared with Usual Care.

INTRODUCTION: Esophagogastric varices are a common complication of portal hypertension and can present with life-threatening bleeding. Definitive endoscopic therapy is via band ligation or sclerotherapy. The former is preferred for esophageal varices, but efficacy is lower in gastric varices (GV). Sclerotherapy with cyanoacrylate (CA) has shown better efficacy and is now recommended as first line therapy for bleeding GV. Studies on long-term efficacy and complications remain limited. CASE DESCRIPTION/METHODS: A 62-year-old woman with NASH cirrhosis (MELD 11) presented with hematemesis. She denied any history of SBP, varices, or encephalopathy. She endorsed a previous history of COVID-19 and had reactive IgG but PCR probe for SARS-CoV-2 was negative. She underwent EGD and was found to have oozing GV along the lesser curvature, which were treated with 4cc of CA achieving hemostasis. The following night she had altered mentation and the blood lactate was increased to 7.2 mmol/L. AST and ALT were also increased. She received broad spectrum antibiotics, and a CT angiogram showed evidence of embolization of CA into the left lobe of the liver. On day 3 her level of consciousness declined and she was intubated for airway compromise. An MRCP confirmed the presence of CA within the left hepatic lobe with associated ischemia. The lactate increased to 20 mmol/L and the blood ammonia level to 700 mcg/dL, with MELD 45. Continuous hemodialysis was started for anuric renal failure. She underwent evaluation for liver transplantation, but cerebral edema and multiorgan failure with refractory acidosis occurred and she died on day 7. DISCUSSION: We present a case of GV treated with CA and the subsequent embolization of CA into the left lobe of the liver. This precipitated acute on chronic liver failure with features of fulminant hepatic failure (FHF) complicated by severe hyperammonemia, cerebral edema, multiorgan failure, and death. Although she had a recent diagnosis of COVID-19, the time course, relatively normal initial inflammatory markers, and imaging suggest that CA embolization was likely the injury that led to fulminant hepatic failure. Given the lack of case reports of CA embolization to the liver causing infarction and few cases to the brain or distant vessels, further research on its long-term safety is warranted. Another novel aspect to this case is the development of FHF in a patient with known cirrhosis