Determinants of survival in patients on extracorporeal membrane oxygenation therapy due to severe covid-19.

BACKGROUND: Severe acute respiratory distress syndrome (ARDS) due to Coronavirus Disease-19 (COVID-19) is associated with high mortality. Although survival on mechanical circulatory support has improved, determinants for better prognosis are still unclear. Here, we report on the outcome of our patient population with the need for mechanical circulatory support due to severe COVID-19 (sCOVID-19) induced ARDS. METHODS: All patients treated with extracorporeal membrane oxygenation (ECMO) for severe ARDS due to sCOVID-19 were analysed. Patients > 18 years of age at the time of initiation of ECMO were included. Pre-existing comorbidities, complications during ECMO implantation, and ECMO runtime were reviewed. The latency to intubation, proning, tracheotomy, and ECMO implantation was analysed. Furthermore, the survival and non-survival population were compared to determine factors in favour of a better outcome. RESULTS: In total, 85 patients were treated with veno-venous membrane oxygenation (vv-ECMO) for severe ARDS in our medical centre. The patient population was predominantly male (83.5%) with a mean patient age of 54.9 years. A history of cardiovascular disease (p = .01), smoking (p < .05), need for vasopressor- (p < .05), and renal replacement therapy (p < .001) was associated with a worse prognosis. Overall survival was 50%. The survival population was significantly younger (p = .004), had a significantly higher body weight (p = .02) and body mass index (BMI) (p = .01). Furthermore, survival was significantly better when vv-ECMO was initiated within 48 h after admission (p < .001). CONCLUSIONS: Pre-existing cardiovascular disease, higher age, history of nicotine abuse, and development of renal failure are associated with poor outcome. Early start of vv-ECMO therapy may lead to better survival in sCOVID-19 patients, although complications during ECMO therapy are associated with a worse prognosis.

Clinical and biochemical endpoints and predictors of response to plasma exchange in septic shock: results from a randomized controlled trial.

BACKGROUND: Recently, a randomized controlled trial (RCT) demonstrated rapid but individually variable hemodynamic improvement with therapeutic plasma exchange (TPE) in patients with septic shock. Prediction of clinical efficacy in specific sepsis treatments is fundamental for individualized sepsis therapy. METHODS: In the original RCT, patients with septic shock of < 24 h duration and norepinephrine (NE) requirement ≥ 0.4 µg/kg/min received standard of care (SOC) or SOC + one single TPE. Here, we report all clinical and biological endpoints of this study. Multivariate mixed-effects modeling of NE reduction was performed to investigate characteristics that could be associated with clinical response to TPE. RESULTS: A continuous effect of TPE on the reduction in NE doses over the initial 24 h was observed (SOC group: estimated NE dose reduction of 0.005 µg/kg/min per hour; TPE group: 0.018 µg/kg/min per hour, p = 0.004). Similarly, under TPE, serum lactate levels, continuously decreased over the initial 24 h in the TPE group, whereas lactate levels increased under SOC (p = 0.001). A reduction in biomarkers and disease mediators (such as PCT (p = 0.037), vWF:Ag (p < 0.001), Angpt-2 (p = 0.009), sTie-2 (p = 0.005)) along with a repletion of exhausted protective factors (such as AT-III (p = 0.026), Protein C (p = 0.012), ADAMTS-13 (p = 0.008)) could be observed in the TPE but not in the SOC group. In a multivariate mixed effects model, increasing baseline lactate levels led to greater NE dose reduction effects with TPE as opposed to SOC (p = 0.004). CONCLUSIONS: Adjunctive TPE is associated with the removal of injurious mediators and repletion of consumed protective factors altogether leading to preserved hemodynamic stabilization in refractory septic shock. We identified that baseline lactate concentration as a potential response predictor might guide future designing of large RCTs that will further evaluate TPE with regard to hard endpoints. Trial registration Retrospectively registered 18th January 2020 at clinicaltrials.gov (Identifier: NCT04231994 ).

High Incidence of Epileptiform Potentials During Continuous EEG Monitoring in Critically Ill COVID-19 Patients.

Objective: To analyze continuous 1- or 2-channel electroencephalograms (EEGs) of mechanically ventilated patients with coronavirus disease 2019 (COVID-19) with regard to occurrence of epileptiform potentials. Design: Single-center retrospective analysis. Setting: Intensive care unit of Hannover Medical School, Hannover, Germany. Patients: Critically ill COVID-19 patients who underwent continuous routine EEG monitoring (EEG monitor: Narcotrend-Compact M) during sedation. Measurements and Main Results: Data from 15 COVID-19 patients (11 men, four women; age: 19-75 years) were evaluated. Epileptiform potentials occurred in 10 of 15 patients (66.7%). Conclusions: The results of the evaluation regarding the occurrence of epileptiform potentials show that there is an unusually high percentage of cerebral involvement in patients with severe COVID-19. EEG monitoring can be used in COVID-19 patients to detect epileptiform potentials.

Mechanical circulatory support in coronavirus disease-2019-positive patients with severe respiratory failure.

OBJECTIVES: Treatment of severe acute respiratory distress syndrome (ARDS) induced by severe acute respiratory syndrome coronavirus 2 has been heavily debated. Our goal was to describe our findings in patients with severe ARDS due to severe coronavirus disease 2019 (sCOVID-19) treated with venovenous extracorporeal membrane oxygenation (vv-ECMO). METHODS: We retrospectively examined all patients treated with vv-ECMO for severe ARDS due to acute respiratory syndrome coronavirus 2. RESULTS: In total, 13 patients were treated with vv-ECMO in our medical centre. The mean patient age was 48.1 years. Most patients were obese (69%) and male (85%). All patients were mechanically ventilated before ECMO. The mean time from intubation to proning was 16.6 h; the time from start of prone therapy to vv-ECMO implantation was 155.1 h. The mean total ECMO run time was 358 h. Significant reduction of positive end-expiratory pressure (P = 0.02), peak pressure (P = 0.001) and minute volume (P = 0.03) could be achieved after implantation of vv-ECMO. All patients showed an inflammatory response. Overall mortality was 30.7%: 1 patient died of mesenteric ischaemia; 3 patients died of multiple organ failure. A worse prognosis was seen in patients with highly elevated concentrations of interleukin-6. CONCLUSIONS: The use of vv-ECMO in patients with sCOVID-19-induced ARDS is safe and associated with improved respiratory ventilation settings. The rate of immune system involvement plays a pivotal role in the development and outcome of sCOVID-19.

Reappearance of effector T cells is associated with recovery from COVID-19.

BACKGROUND: Elucidating the role of T cell responses in COVID-19 is of utmost importance to understand the clearance of SARS-CoV-2 infection. METHODS: 30 hospitalized COVID-19 patients and 60 age- and gender-matched healthy controls (HC) participated in this study. We used two comprehensive 11-colour flow cytometric panels conforming to Good Laboratory Practice and approved for clinical diagnostics. FINDINGS: Absolute numbers of lymphocyte subsets were differentially decreased in COVID-19 patients according to clinical severity. In severe disease (SD) patients, all lymphocyte subsets were reduced, whilst in mild disease (MD) NK, NKT and γδ T cells were at the level of HC. Additionally, we provide evidence of T cell activation in MD but not SD, when compared to HC. Follow up samples revealed a marked increase in effector T cells and memory subsets in convalescing but not in non-convalescing patients. INTERPRETATION: Our data suggest that activation and expansion of innate and adaptive lymphocytes play a major role in COVID-19. Additionally, recovery is associated with formation of T cell memory as suggested by the missing formation of effector and central memory T cells in SD but not in MD. Understanding T cell-responses in the context of clinical severity might serve as foundation to overcome the lack of effective anti-viral immune response in severely affected COVID-19 patients and can offer prognostic value as biomarker for disease outcome and control. FUNDING: Funded by State of Lower Saxony grant 14-76,103-184CORONA-11/20 and German Research Foundation, Excellence Strategy - EXC2155"RESIST"-Project ID39087428, and DFG-SFB900/3-Project ID158989968, grants SFB900-B3, SFB900-B8.

Corrigendum to: Maintenance Immunosuppression Is Associated With Better Outcome in the 2017/2018 Influenza Epidemic.

[This corrects the article DOI: 10.1093/ofid/ofz381.].

Therapeutic plasma exchange in acute on chronic liver failure.

BACKGROUND: Acute on chronic liver failure (ACLF) has been identified as a distinct syndrome due to acute decompensation of liver cirrhosis accompanied by extra-hepatic organ failure, primarily caused by an overwhelming systemic immune response. Therapeutic plasma exchange (TPE) has been demonstrated in a randomized controlled trial to improve transplant free survival in acute liver failure. Here we investigated if TPE might have comparable beneficial effects in patients with ACLF. METHODS: Thirty-one patients with ACLF that were treated with TPE were enrolled into this retrospective analysis and 1:1 matched to an ACLF cohort treated with standard medical therapy (SMT) only. RESULTS: Patients considered for a bridge to recovery (n = 21 each group) approach had a 30-day mortality >90% that was not improved by TPE (P = .185). Deaths occurred in the SMT group at significant earlier time points compared to the patients treated with TPE (mortality at 5 days: 33.3% for TPE and 66.7% for SMT, P = .048). However, patients who received TPE as a bridge to transplant strategy (n = 10) survived in 60% of cases and demonstrated 24 hours after study inclusion a stabilization of organ dysfunction (organ failures at inclusion: 4 (3-5) vs 24 hours after inclusion: 3 (2-4), P = .031 and CLIF-C-ACLF score: 64 (49-76) vs 54 (49-66), P = .043) not seen in SMT patients. CONCLUSIONS: Although these retrospective data need to be interpreted with caution, they suggest that TPE in ACLF patients is feasible but not suitable as a bridge to recovery strategy. In selected patients TPE might assist as bridge to transplant.

Long-term outcomes after intraoperative extracorporeal membrane oxygenation during lung transplantation.

INTRODUCTION: Over the past decade, extracorporeal membrane oxygenation (ECMO) has replaced cardiopulmonary bypass (CPB) for cardiopulmonary support during lung transplantation at our institution. In this study, we present our experience using intraoperative ECMO in isolated lung transplantation and evaluate its impact on long-term graft function and survival. METHODS: All patients undergoing isolated lung transplantation with or without ECMO support between January 2010 and June 2019 were evaluated. Patients transplanted using CPB were excluded. Peri-operative and follow-up results from our database and patient charts were analyzed. Follow-up continued until September 1, 2019 (median, 3.34 years). RESULTS: In total, 311 of 1,161 lung transplant recipients (27%) received intraoperative ECMO, with 24 (2%) patients further requiring CPB. None of the remaining 826 (71%) patients required intraoperative cardiopulmonary support. ECMO patients exhibited higher pre-transplant surgical risk profiles and endured more complicated early post-operative courses than those without ECMO (in-hospital mortality, 10.9% vs 2.3%; p < 0.001). Inevitably, this resulted in poorer overall graft survival among ECMO recipients (p = 0.0025). However, correcting for patients surviving to hospital discharge, no difference in survival between groups was observed (5-year survival, 71% vs 72%; p = 0.56). Similarly, freedom from chronic lung allograft dysfunction, biopsy-confirmed cellular rejection, or need for pulsed-steroid therapy did not differ between the groups (p = 0.99, p = 0.78, and p = 0.93, respectively). CONCLUSIONS: Compared with patients not requiring cardiopulmonary support, ECMO recipients endured a more complicated peri-operative and early post-operative course. However, among those surviving to hospital discharge, no differences in long-term complications or outcomes were observed.

Enoximone in status asthmaticus.

In a patient with severe status asthmaticus, enoximone, a phosphodiesterase-3 inhibitor, caused immediate bronchodilation http://bit.ly/38UYpUn.

A Retrospective Analysis of Nonocclusive Mesenteric Ischemia in Medical and Surgical ICU Patients: Clinical Data on Demography, Clinical Signs, and Survival.

BACKGROUND: To analyze demography, clinical signs, and survival of intensive care patients diagnosed with nonocclusive mesenteric ischemia (NOMI) and to evaluate the effect of a local intra-arterial prostaglandin therapy. METHODS: Retrospective observational study screening 455 intensive care patients with acute arterial mesenteric perfusion disorder in a tertiary care hospital within the past 8 years. Lastly, 32 patients with NOMI were enrolled, of which 11 received local intra-arterial prostaglandin therapy. The diagnosis of NOMI was based on the clinical presentation and established biphasic computed tomography criteria. Clinical and biochemical data were obtained 24 hours before, at the time, and 24 hours after diagnosis. RESULTS: Patients were 60.5 (49.3-73) years old and had multiple comorbidities. Most of them were diagnosed with septic shock requiring high doses of norepinephrine (NE: 0.382 [0.249-0.627] µg/kg/min). The Sequential Organ Failure Assessment (SOFA) score was 18 (16-20). A decrease in oxygenation (Pao 2/Fio 2), pH, and bicarbonate and an increase in international normalized ratio, lactate, bilirubin, leucocyte count, and NE dose were early indicators of NOMI. Median SOFA score significantly increased in the last 24 hours before diagnosis of NOMI (16 vs 18, P < .0001). Overall, 28-day mortality was 75% (81% nonintervention vs 64% intervention cohort; P = .579). Median SOFA scores 24 hours after intervention increased by +5% in the nonintervention group and decreased by 5.5% in the intervention group (P = .0059). CONCLUSIONS: Our data suggest that NOMI is a detrimental disease associated with progressive organ failure and a high mortality. Local intra-arterial prostaglandin application might hold promise as a rescue treatment strategy. These data encourage future randomized controlled trials are desirable.

Maintenance Immunosuppression Is Associated With Better Outcome in the 2017/2018 Influenza Epidemic.

BACKGROUND: The impact of immunosuppression on outcomes in influenza is insufficiently understood. We analyzed the morbidity and mortality of immunocompetent (IC) vs immunosuppressed (IS) patients with influenza A and B in the 2017/2018 season. METHODS: Patients with proven influenza in a German tertiary care hospital were analyzed for hospitalization, intensive care unit (ICU) admission, and mortality. Causes for IS were organ and bone marrow transplantation, AIDS, chemotherapy, and medical immunosuppression. RESULTS: In total, 227 patients were included in this analysis (IC, n = 118 [52%]; IS, n = 109 [48%]). Hospitalization (71% vs 91%; P < .001) and ICU admission (7% vs 23%; P = .001) were less frequent in the IS compared with the IC group. IC patients had a higher need for invasive ventilation (20% vs 5%; P = .001), vasopressors (19% vs 4%; P < .001), and renal replacement therapy (15% vs 3%; P = .002). Influenza-associated cardiomyopathy was found in 18% of IC vs 2% of IS patients (P < .001). The 30-day in-hospital mortality was 6.6%, 10.2% in the IC group and 2.8% in the IS group (hazard ratio IS group, 0.259; 95% confidence interval [CI], 0.113-0.855; P = .023). Immunosuppression was associated with reduced mortality (odds ratio, 0.25; 95% CI, 0.07-0.91; P = .036). CONCLUSIONS: We observed that IS was not associated with a worse outcome in this influenza cohort. Due to the presence of both confounding and referral and selection bias, the conclusion that immunosuppression reduces mortality cannot be drawn. Prospective studies investigating the influence of baseline immunosuppression on severity of influenza infection are desirable.

Therapeutic plasma exchange in acute liver failure.

BACKGROUND: Multi-organ dysfunction in acute liver failure (ALF) has been attributed to a systemic inflammatory response directly triggered by the injured liver. High-volume therapeutic plasma exchange (HV-TPE) has been demonstrated in a large randomized controlled trial to improve survival. Here, we investigated if a more cost-/ resource effective low-volume (LV) TPE strategy might have comparable beneficial effects. METHODS: This retrospective study evaluated the effect of LV-TPE on remote organ failure, hemodynamical and biochemical parameters as well as on survival in patients with ALF. Twenty patients treated with LV-TPE in addition to standard medical therapy (SMT) were identified and 1:1 matched to a historical ALF cohort treated with SMT only. Clinical and biochemical parameters were recorded at admission to the intensive care unit and the following 7 days after LV-TPE. RESULTS: Mean arterial pressure increased following first LV-TPE treatments (d0: 68 [61-75] mm Hg vs d7: 88 [79-98] mm Hg, P = .003) and norepinephrine dose was reduced (d0: 0.264 [0.051-0.906] µg/kg/min vs d3: 0 [0-0.024] µg/kg/min, P = .016). Multi-organ dysfunction was significantly diminished following LV-TPE (CLIF-SOFA d0: 17 [13-20] vs d7: 7 [3-11], P = .001). Thirty-day in-hospital survival was 65% in the LV-TPE cohort and 50% in the SMT cohort (Hazard-ratio for TPE: 0.637; 95% CI: 0.238-1.706, P = .369). CONCLUSIONS: Patients treated with LV-TPE showed improved surrogate parameters comparable with the effects reported with HV-TPE. These data need to be interpreted with caution due to their retrospective character. Future controlled studies are highly desirable.

Early therapeutic plasma exchange in septic shock: a prospective open-label nonrandomized pilot study focusing on safety, hemodynamics, vascular barrier function, and biologic markers.

BACKGROUND: Given the pathophysiological key role of the host response to an infection rather than the infection per se, an ideal therapeutic strategy would also target this response. This study was designed to demonstrate safety and feasibility of early therapeutic plasma exchange (TPE) in severely ill individuals with septic shock. METHODS: This was a prospective single center, open-label, nonrandomized pilot study enrolling 20 patients with early septic shock (onset < 12 h) requiring high doses of norepinephrine (NE; > 0.4 µg/kg/min) out of 231 screened septic patients. Clinical and biochemical data were obtained before and after TPE. Plasma samples were taken for ex-vivo stimulation of human umbilical vein endothelial cells (HUVECs) to analyze barrier function (immunocytochemistry and transendothelial electrical resistance (TER)). Cytokines were measured by cytometric bead array (CBA) and enzyme-linked immunosorbent assays (ELISAs). An immediate response was defined as > 20% NE reduction from baseline to the end of TPE. RESULTS: TPE was well tolerated without the occurrence of any adverse events and was associated with a rapid reduction in NE (0.82 (0.61-1.17) vs. 0.56 (0.41-0.78) µg/kg/min, p = 0.002) to maintain mean arterial pressure (MAP) above 65 mmHg. The observed 28-day mortality was 65%. Key proinflammatory cytokines and permeability factors (e.g., interleukin (IL)-6, IL-1b, and angiopoietin-2) were significantly reduced after TPE, while the protective antipermeability factor angiopoietin-1 was not changed. Ex-vivo stimulation of HUVECs with plasma obtained before TPE induced substantial cellular hyperpermeability, which was completely abolished with plasma obtained after TPE. CONCLUSIONS: Inclusion of early septic shock patients with high doses of vasopressors was feasible and TPE was safe. Rapid hemodynamic improvement and favorable changes in the cytokine profile in patients with septic shock were observed. It has yet to be determined whether early TPE also improves outcomes in this patient cohort. An appropriately powered multicenter randomized controlled trial is desirable. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03065751 . Retrospectively registered on 28 February 2017.

Application of the Liver Maximum Function Capacity Test in Acute Liver Failure: A Helpful Tool for Decision-Making in Liver Transplantation?

Background. Despite aggressive intensive medical management acute liver failure (ALF) may require high-urgency liver transplantation (LTx). Available prognostic scores do not apply for all patients; reliable tools to identify individuals in need of LTx are highly required. The liver maximum function capacity test (LiMAx) might represent an appropriate option. Referring to a case of ALF after Amanita phalloides-intoxication the potential of the LiMAx-test in this setting is discussed. Presentation of Case. LiMAx was performed in a 27-year-old patient prior to and after high-urgency LTx. In accordance with clinical appearance of hepatic encephalopathy, coagulopathy, and acute kidney failure, the LiMAx-test constituted a fulminant course of ALF with hardly any detectable metabolic activity. Following LTx with a marginal donor organ (95% hepatosteatosis), uptake of liver function was demonstrated by postoperative increase of the LiMAx-value. The patient was discharged from hospital on postoperative day 26. Discussion. ALF often is associated with a critical state of the patient that requires almost immediate decision-making regarding further therapy. Application of a noninvasive liver function test might help to determine the prognosis of ALF and support decision-making for or against LTx as well as acceptance of a critical donor organ in case of a critically ill patient.

Treatment of amitriptyline intoxications by extended high cut-off dialysis.

Antidepressants, especially amitriptyline, are among the most frequent drug classes involved in intoxications. Despite its small molecular weight, amitriptyline is not considered to be eliminated by extracorporeal treatment methods due to its high protein binding and large volume of distribution. New high cut-off dialysers have so far not been used for removal of amitriptyline. We report two cases of amitriptyline poisoning in which we measured the amitriptyline elimination using extended high cut-off (HCO) dialysis. Despite dialyser clearances of 33 and 58 mL/min, resulting in the reduction of initial serum concentrations by ∼30%, only 211 and 920 µg of amitryptilin, respectively, (<3% of the ingested amount) could be recovered in the total collected dialysate. Hence, due to the high volume of distribution of amitriptyline, even HCO dialysis does not contribute substantially to the extracorporeal removal of amitryptilin.

Veno-veno-arterial extracorporeal membrane oxygenation for respiratory failure with severe haemodynamic impairment: technique and early outcomes.

OBJECTIVES: Patients with respiratory failure may benefit from veno-venous and veno-arterial extracorporeal membrane oxygenation (ECMO) support. We report on our initial experience of veno-veno-arterial (v-v-a) ECMO in patients with respiratory failure. METHODS: Between January 2012 and February 2014, 406 patients required ECMO support at our institution. Here, we retrospectively analysed the characteristics and outcomes of patients commenced on either veno-venous or veno-arterial ECMO due to respiratory failure, and then switched to v-v-a ECMO. RESULTS: Ten (2%) patients proceeded to v-v-a ECMO. The underlying conditions were acute respiratory distress syndrome (n = 3), end-stage pulmonary fibrosis (n = 5) and respiratory failure after major thoracic surgery (n = 1) and Caesarean section (n = 1). In all of these patients, ECMO was initially started as veno-venous (n = 9) or veno-arterial (n = 1) ECMO but was switched to a veno-veno-arterial (v-v-a) approach after a mean of 2 (range, 0-7) days. Reasons for switching were: haemodynamic instability (right heart failure, n = 5; pericardial tamponade, n = 1; severe mitral valve regurgitation, n = 1; haemodynamic instability following cardiopulmonary resuscitation, n = 1 and evidence of previously unknown atrial septal defect with pulmonary hypertension and Eisenmenger syndrome, n = 1) and upper-body hypoxaemia (n = 1). ECMO-related complications were bleeding (n = 3) and leg ischaemia (n = 2). Seven patients were successfully taken off ECMO with 4 being bridged to recovery and a further 3 to lung transplantation after a mean of 11 (range, 9-18) days. Five patients survived until hospital discharge and all of them were alive at the end of the follow-up. CONCLUSIONS: Veno-veno-arterial ECMO is a technically feasible rescue strategy in treating patients presenting with combined respiratory and haemodynamic failure.