Incidence of heparin resistance and heparin failure in patients receiving extracorporeal membrane oxygenation - an exploratory retrospective analysis

Objectives: Unfractionated heparin (UFH) remains the anticoagulation of choice at most centres for patients receiving extracorporeal membrane oxygenation (ECMO). One disadvantage of UFH relies on its individual dosing requirement to achieve target values. In this context heparin resistance has been described, defined as doses exceeding 35,000 IU UFH/d. However, the incidence of heparin resistance and its association with thromboembolic complications despite anticoagulation within target ranges remains unknown. Method(s): This retrospective study included adults receiving venovenous (VV) and venoarterial (VA) ECMO, or extracorporeal CO2-removal (ECCO2R) between 2010 and May 2022. The primary outcome was the incidence of heparin resistance (>35,000 IU of UFH/d). Secondary outcomes were heparin failure (thromboembolic complications despite anticoagulation within target ranges) and survival. A multivariable poisson regression model was fitted to analyse the effect of heparin resistance, COVID-19 and ECMO type on the incidence rate of thromboembolic events. Result(s): Of 197 included patients, 33 (16.8%) had heparin resistance. Patients with COVID-19 (n=51) had a higher rate of heparin resistance compared to nonCOVID-19 patients (37% vs. 9.6%, P<0.001). Thromboembolic complications occurred at a rate of 5.89/100 ECMO days. There was a significant effect of COVID-19 (incidence rate ratio (IRR) 2.12, 95% confidence interval (CI) 1.4 to 3.3, P<0.001) and ECMO type (VA ECMO: IRR 2.35;95% CI 1.43 to 3.87, P<0.001;ECCO2R: IRR 2.63, 95% CI 1.37 to 4.9, P=0.003;reference VV ECMO) on incidence rate of thromboembolic events, but not of heparin resistance (IRR 1.11, 95% CI 0.7 to 1.76, P=0.7). ECMO duration was longer (25d (IQR 11-33) vs. 8d (IQR 4-18), P<0.001) in patients with heparin resistance, but hospital survival did not differ (23 (70%) vs. 91 (57%), P=0.2). Conclusion(s): The study revealed a high incidence of heparin failure in ECMO patients, especially in those with COVID-19. Heparin resistance had no effect on the incidence rate of thromboembolic events, whereas our data suggest an increased risk in patients with COVID19, VA ECMO and ECCO2R.

Analysis of Estonian Ecmo Registry Data of Covid Outbrake 2020 to 2022

We launched Estonian nationwide ECMO registry in 2021 including data of all patients supported with ECLS in both ECMO centres - Tartu University Hospital and North Estonia Medical Centre. For the completeness of Registry all retrospective data were added back from 2009. Dataset includes patient demographics, diagnoses, ICU-, hospital- and 12 month survival, ECLS details and complications. To date, the registry contains data of 301 patients. Since January 2020, 65 confirmed Covid-19 patients have received ECLS support: VV-ECMO was used 55, ECCO2R 7, VA support 1 and eCPR in 2 instances. The primary outcome in our analysis was in-hospital death. Secondary outcome was to compare in-hospital mortality and length of stay of Covid-confirmed patients to the 54 non-Covid ARDS patients treated with VV-ECMO. Finding(s): Data for 55 adult patients with Covid-19 who received VV-ECMO support were available and included to this study. Of these 19(34.5%) were discharged home or to rehabilitation centre, 6(10.9%) were still in hospital at a time of analysis and 22(40.0%) died. One patient was bridged to successful lung transplantation. We also supported two pregnant patients with good maternal and neonatal outcomes. Comparing hospital mortality of Covid-confirmed cases to 54 non-Covid adult ARDS patients, hospital mortality was similar between the groups - 44.9% (22/49) and 46.2% (34/52) respectively. For those who were discharged alive, hospital LOS was longer for Covid-confirmed cases compared to non-Covid patients (mean 59 vs 50 days, respectively). Interpretation(s): In patients with Covid-19 who received ECMO, observed outcome supports existing recommendations to consider use of ECMO in refractory Covid-19 related respiratory failure when performed in experienced centres. Registry can also be used to coordinate ECMO beds, equipment and personnel as resources become constrained. We constantly monitored availability of ECMO beds and agreed on common indications for VV ECMO in covid patients. Further analysis will concentrate on 12 month survival and functional outcome.Copyright © 2022

Extracorporeal life support as a bridge to lung transplantation: Where are we now?

The number of lung transplant procedures performed internationally is increasing but the donor organ pool is insufficient to meet demand and waiting list mortality is unacceptably high. As survival rates for patients with acute respiratory distress syndrome managed on extracorporeal life support (ECLS) have steadily improved, a potential role for ECLS to support critically ill patients awaiting a donor organ match has emerged. We explore the rapidly evolving landscape of ECLS as a bridge to lung transplantation with review of the patient selection criteria, predictors of survival, modes of pre and peri-transplant support, and the importance of a holistic multidisciplinary approach to care. Finally, we consider innovations that are envisaged to increase the accessibility, safety, and effectiveness of ECLS delivery for future lung transplant candidates.

Predictors of Mortality in Acute Respiratory Failure Patients Treated with Extracorporeal CO2 Removal

Extracorporeal CO2 removal (ECCO2R) is an effective therapy for correcting hypercapnia and respiratory acidosis. However, appropriate patient selection for optimal ECCO2R outcomes is not well defined. The goal of this retrospective, multicenter study was to determine patient and ECCO2R therapy characteristics which predict mortality in acute respiratory failure patients treated with the Hemolung ECCO2R system (ALung Technologies). The Hemolung Registry was queried for patients with acute respiratory failure. The Registry contains patient demographics, baseline and on- ECCO2R physiologic parameters, ICU survival and Hemolung performance data. Predictors of ICU survival were identified using a multivariable logistical regression analysis. 159 Hemolung patients were included in the analysis. Patients primarily had COVID-19 (55%) or non-COVID-19 ARDS (36%). Survival to ICU discharge was 41%. The median age of survivors was lower (49 vs 58 years), the use of adjunct therapies was lower in survivors (35.4% vs 64.9%), and a greater proportion of survivors received the recommended level of anticoagulation (43.1% vs 23.4%). ECCO2R complications were not significantly different between ICU survivors and non-survivors. COVID-19 diagnosis and a P/F < 100 at the start of Hemolung therapy were each independently associated with ICU mortality. This is the first study specifically evaluating patient and ECCO2R therapy characteristics that independently predict mortality in patients presenting with acute respiratory failure. The results of this study can provide insight in patient selection for future clinical trials and real-world use. Due to the retrospective nature of this study survival to hospital discharge data was not available.

Real-World Use of Extracorporeal CO2 Removal (ECCO2R) to Correct Respiratory Acidosis: Analysis of the Hemolung Registry

Hypercapnia and respiratory acidosis lead to increased morbidity and mortality in critically ill patients. Extracorporeal CO2 removal (ECCO2R) can rapidly correct pH and PaCO2 as a treatment for refractory, hypercapnic respiratory failure. Current clinical evidence for the benefits of ECCO2R is primarily limited to case series and single-center studies. The Hemolung (ALung Technologies, Inc., Pittsburgh, PA) is the only FDA cleared ECCO2R system and has been utilized to treat greater than 1,000 patients world-wide. The purpose of this study was to evaluate real-world evidence of the Hemolung ECCO2R system for the treatment of hypercapnic respiratory failure across a range of primary diagnoses. Methods: The Hemolung Registry was queried for patients with a baseline, pre-Hemolung pH < 7.35. Patients receiving either noninvasive or invasive ventilation were included in the analysis. Physiological benefits of Hemolung therapy were evaluated using a mixed model for repeated measures based on changes in pH and PaCO2 after 4-6 hrs and 16-35 hrs of Hemolung therapy compared to the baseline value. The model was used to calculate two-sided 95% confidence intervals and associated nominal p-values. Additional markers of clinical improvement included avoidance of intubation, survival to decannulation, and Hemolung CO2 removal rate and duration of use. Adverse events were also analyzed based on patient harm. Results: 176 Hemolung patients were included in the analysis. Multiple primary diagnoses were represented: 31% ARDS, 22% COPD exacerbation, 32% COVID-19, and 15% Other. Median CO2 removal by the Hemolung during the first day of therapy was 88 mL/min and resulted in a concomitant correction of pH from a median of 7.20 to 7.35 (p<0.001) and median PaCO2 correction of 81.7 to 57.0 mmHg (p<0.001). Correction of respiratory acidosis was independent of primary diagnosis, age, and BMI. 69% (112/162) of patients survived to de-cannulation. 86% (19/22) of patients failing NIV avoided intubation. There were no unanticipated complications, and the majority of adverse events did not require medical intervention or discontinuation of Hemolung therapy. 3 deaths associated with Hemolung therapy occurred. Conclusion: These data represent the largest reported analysis of ECCO2R therapy to treat a diverse population of hypercapnic respiratory failure patients. The results demonstrate significant correction of pH and PaCO2 within the first day of Hemolung therapy without significant adverse events. Data from forthcoming RCTs will shed further light on whether these physiologic benefits translate to improved outcomes compared to current standard of care.

Real-World Evidence of ECCO2R to Correct Respiratory Acidosis: Analysis of the Hemolung Registry

Rationale: Hypercapnia and respiratory acidosis lead to increased morbidity and mortality in critically ill patients. Extracorporeal CO2 removal (ECCO2R) can rapidly correct pH and PaCO2 as a treatment for refractory, hypercapnic respiratory failure. Current clinical evidence for the benefits of ECCO2R is primarily limited to case series and single-center studies. The Hemolung (ALung Technologies) is the only FDA cleared ECCO2R system and has been utilized to treat greater than 1,000 patients world-wide. The purpose of this study was to evaluate real-world evidence of the Hemolung ECCO2R system for the treatment of hypercapnic respiratory failure across a range of primary diagnoses. Methods: The Hemolung Registry was queried for patients with a baseline, pre- Hemolung pH < 7.35. Patients receiving either noninvasive or invasive ventilation were included in the analysis. Physiological benefits of Hemolung therapy were evaluated using a mixed model for repeated measures based on changes in pH and PaCO2 after 4-6 hrs and 16-35 hrs of Hemolung therapy compared to the baseline value. The model was used to calculate two-sided 95% confidence intervals and associated nominal p-values. Additional markers of clinical improvement included avoidance of intubation, survival to decannulation, and Hemolung CO2 removal rate and duration. Adverse events were also analyzed based on patient harm. Results:176 Hemolung patients were included in the analysis. Multiple primary diagnoses were represented: 31% ARDS, 22% COPD exacerbation, 32% COVID-19, and 15% Other. Median duration of Hemolung therapy was 6.0 days. Median CO2 removal by the Hemolung during the first day of therapy was 88 mL/min and resulted in a concomitant correction of pH from a median of 7.20 to 7.35 (p<0.001) and median PaCO2 correction of 81.7 to 57.0 mmHg (p<0.001). Correction of respiratory acidosis was independent of primary diagnosis, age, and BMI. 69% (112/162) of patients survived to decannulation. 86% (19/22) of patients failing NIV avoided intubation. There were no unanticipated complications, and the majority of adverse events did not require medical intervention or discontinuation of Hemolung therapy. 3 deaths associated with Hemolung therapy occurred. Conclusions: These data represent the largest reported analysis of ECCO2R therapy to treat a diverse population of hypercapnic respiratory failure patients. The results demonstrate significant correction of pH and PaCO2 within the first day of Hemolung therapy without significant adverse events. Data from forthcoming RCTs will shed further light on whether these physiologic benefits translate to improved outcomes compared to current standard of care.

Venovenous extracorporeal CO2 removal to support ultraprotective ventilation in moderate-severe acute respiratory distress syndrome: A systematic review and meta-analysis of the literature.

BACKGROUND: A strategy that limits tidal volumes and inspiratory pressures, improves outcomes in patients with the acute respiratory distress syndrome (ARDS). Extracorporeal carbon dioxide removal (ECCO2R) may facilitate ultra-protective ventilation. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of venovenous ECCO2R in supporting ultra-protective ventilation in moderate-to-severe ARDS. METHODS: MEDLINE and EMBASE were interrogated for studies (2000-2021) reporting venovenous ECCO2R use in patients with moderate-to-severe ARDS. Studies reporting ≥10 adult patients in English language journals were included. Ventilatory parameters after 24 h of initiating ECCO2R, device characteristics, and safety outcomes were collected. The primary outcome measure was the change in driving pressure at 24 h of ECCO2R therapy in relation to baseline. Secondary outcomes included change in tidal volume, gas exchange, and safety data. RESULTS: Ten studies reporting 421 patients (PaO2:FiO2 141.03 mmHg) were included. Extracorporeal blood flow rates ranged from 0.35-1.5 L/min. Random effects modelling indicated a 3.56 cmH2O reduction (95%-CI: 3.22-3.91) in driving pressure from baseline (p < .001) and a 1.89 mL/kg (95%-CI: 1.75-2.02, p < .001) reduction in tidal volume. Oxygenation, respiratory rate and PEEP remained unchanged. No significant interactions between driving pressure reduction and baseline driving pressure, partial pressure of arterial carbon dioxide or PaO2:FiO2 ratio were identified in metaregression analysis. Bleeding and haemolysis were the commonest complications of therapy. CONCLUSIONS: Venovenous ECCO2R permitted significant reductions in ∆P in patients with moderate-to-severe ARDS. Heterogeneity amongst studies and devices, a paucity of randomised controlled trials, and variable safety reporting calls for standardisation of outcome reporting. Prospective evaluation of optimal device operation and anticoagulation in high quality studies is required before further recommendations can be made.

Effect of extracorporeal carbon dioxide removal on respiratory quotient measured by indirect calorimetry: Unravelling the mystery.

NEW FINDINGS: What is the main observation in this case? Several studies have reported progressive hypoxaemia once extracorporeal carbon dioxide removal is started in patients with hypercapnic respiratory failure, possibly attributable to an altered respiratory quotient. What insights does it reveal? In this quality control report, we show that the respiratory quotient exhibits only minimal alteration when extracorporeal carbon dioxide removal is started and assume that the progressive hypoxaemia is attributable to an increase in intrapulmonary shunt. ABSTRACT: The use of extracorporeal carbon dioxide removal (ECCO2 R) has been proposed in patients with acute respiratory distress syndrome to achieve lung-protective ventilation and in patients with selective hypercapnic respiratory failure. However, several studies have reported progressive hypoxaemia, as expressed by a need to increase the inspired oxygen fraction (Fi O2 ) to maintain adequate oxygenation or by a decrease in the ratio of arterial oxygen tension (Pa O2 ) to Fi O2 once ECCO2 R is started. We present the case of a patient who was admitted to the intensive care unit for a coronavirus disease 2019 pneumonia and who was intubated because of hypercapnic respiratory insufficiency. Extracorporeal carbon dioxide removal was started, and the patient subsequently developed progressive hypoxaemia. To test whether the hypoxaemia was attributable to the ECCO2 R, blood samples were taken in different settings: (1) 'no ECCO2 R', blood flow 150 ml/min with a ECCO2 R gas flow of 0 L/min; and (2) 'with ECCO2 R', blood flow 400 ml/min with gas flow 12 L/min. We measured Pa O2 , alveolar oxygen tension, Pa O2 /Fi O2 , alveolar-arterial oxygen tension difference, arterial carbon dioxide tension and the respiratory quotient (RQ) by indirect calorimetry in each setting. The RQ was 0.60 without ECCO2 R and 0.57 with ECCO2 R. The alveolar oxygen tension was 220.4 mmHg without ECCO2 R and increased to 240.3 mmHg with ECCO2 R, whereas Pa O2 /Fi O2 decreased from 177 to 171. Our study showed only a minimal change in RQ when ECCO2 R was started. We were the first to measure the RQ directly, before and after the initiation of ECCO2 R, in a patient with hypercapnic respiratory failure.

Decompressive hemicraniectomy for acute ischemic stroke: A neurosurgical view in a pandemic COVID-19 time highlights of literature.

Background and purpose: The novel coronavirus, SARS-CoV-2, which was identified after the outbreak in Wuhan, China, in December 2019, has kept the whole world in tenterhooks due to its severe life-threatening nature of the infection. The World Health Organization (WHO) declared coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 a pandemic in 2020, an unprecedented challenge, having a high contagious life-threatening condition with unprecedented impacts for worldwide societies and health care systems. Neurologic symptoms related to SARS-CoV-2 have been described recently in the literature, and acute cerebrovascular disease is one of the most serious complications. The occurrence of large-vessel occlusion in young patients with COVID-19 infection has been exceedingly rare. In this article, we describe the profile of patients undergoing decompressive craniectomy for the treatment of intracranial hypertension by stroke associated with COVID-19 published so far. A narrative review of the central issue in focus was designed: decompressive craniectomy in a pandemic time.

Application of extracorporeal carbon dioxide removal combined with continuous blood purification therapy in ARDS with hypercapnia in patients with critical COVID-19.

INTRODUCTION: Coronavirus disease-19 (COVID-19) is a new type of epidemic pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The population is generally susceptible to COVID-19, which mainly causes lung injury. Some cases may develop severe acute respiratory distress syndrome (ARDS). Currently, ARDS treatment is mainly mechanical ventilation, but mechanical ventilation often causes ventilator-induced lung injury (VILI) accompanied by hypercapnia in 14% of patients. Extracorporeal carbon dioxide removal (ECCO2R) can remove carbon dioxide from the blood of patients with ARDS, correct the respiratory acidosis, reduce the tidal volume and airway pressure, and reduce the incidence of VILI. CASE REPORT: Two patients with critical COVID-19 combined with multiple organ failure undertook mechanical ventilation and suffered from hypercapnia. ECCO2R, combined with continuous renal replacement therapy (CRRT), was conducted concomitantly. In both cases (No. 1 and 2), the tidal volume and positive end-expiratory pressure (PEEP) were down-regulated before the treatment and at 1.5 hours, one day, three days, five days, eight days, and ten days after the treatment, together with a noticeable decrease in PCO2 and clear increase in PO2, while FiO2 decreased to approximately 40%. In case No 2, compared with the condition before treatment, the PCO2 decreased significantly with down-regulation in the tidal volume and PEEP and improvement in the pulmonary edema and ARDS after the treatment. CONCLUSION: ECCO2R combined with continuous blood purification therapy in patients with COVID-19 who are criti-cally ill and have ARDS and hypercapnia might gain both time and opportunity in the treatment, down-regulate the ventilator parameters, reduce the incidence of VILI and achieve favorable therapeutic outcomes.

ECCO2R in 12 COVID-19 ARDS Patients With Extremely Low Compliance and Refractory Hypercapnia.

Purpose: A phenotype of COVID-19 ARDS patients with extremely low compliance and refractory hypercapnia was found in our ICU. In the context of limited number of ECMO machines, feasibility of a low-flow extracorporeal carbon dioxide removal (ECCO2R) based on the renal replacement therapy (RRT) platform in these patients was assessed. Methods: Single-center, prospective study. Refractory hypercapnia patients with COVID-19-associated ARDS were included and divided into the adjusted group and unadjusted group according to the level of PaCO2 after the application of the ECCO2R system. Ventilation parameters [tidal volume (VT), respiratory rate, and PEEP], platform pressure (Pplat) and driving pressure (DP), respiratory system compliance, arterial blood gases, and ECCO2R system characteristics were collected. Results: Twelve patients with refractory hypercapnia were enrolled, and the PaCO2 was 64.5 [56-88.75] mmHg. In the adjusted group, VT was significantly reduced from 5.90 ± 0.16 to 5.08 ± 0.43 ml/kg PBW; DP and Pplat were also significantly reduced from 23.5 ± 2.72 mmHg and 29.88 ± 3.04 mmHg to 18.5 ± 2.62 mmHg and 24.75 ± 3.41 mmHg, respectively. In the unadjusted group, PaCO2 decreased from 94 [86.25, 100.3] mmHg to 80 [67.50, 85.25] mmHg but with no significant difference, and the DP and Pplat were not decreased after weighing the pros and cons. Conclusions: A low-flow ECCO2R system based on the RRT platform enabled CO2 removal and could also decrease the DP and Pplat significantly, which provided a new way to treat these COVID-19 ARDS patients with refractory hypercapnia and extremely low compliance. Clinical Trial Registration: https://www.clinicaltrials.gov/, identifier NCT04340414.

Physiologic Improvement in Respiratory Acidosis Using Extracorporeal Co2 Removal With Hemolung Respiratory Assist System in the Management of Severe Respiratory Failure From Coronavirus Disease 2019.

OBJECTIVES: About 15% of hospitalized coronavirus disease 2019 patients require ICU admission, and most (80%) of these require invasive mechanical ventilation. Lung-protective ventilation in coronavirus disease 2019 acute respiratory failure may result in severe respiratory acidosis without significant hypoxemia. Low-flow extracorporeal Co2 removal can facilitate lung-protective ventilation and avoid the adverse effects of severe respiratory acidosis. The objective was to evaluate the efficacy of extracorporeal Co2 removal using the Hemolung Respiratory Assist System in correcting severe respiratory acidosis in mechanically ventilated coronavirus disease 2019 patients with severe acute respiratory failure. DESIGN: Retrospective cohort analysis of patients with coronavirus disease 2019 mechanically ventilated with severe hypercapnia and respiratory acidosis and treated with low-flow extracorporeal Co2 removal. SETTING: Eight tertiary ICUs in the United States. PATIENTS: Adult patients supported with the Hemolung Respiratory Assist System from March 1, to September 30, 2020. INTERVENTIONS: Extracorporeal Co2 removal with Hemolung Respiratory Assist System under a Food and Drug Administration emergency use authorization for coronavirus disease 2019. MEASUREMENTS AND MAIN RESULTS: The primary outcome was improvement in pH and Paco2 from baseline. Secondary outcomes included survival to decannulation, mortality, time on ventilator, and adverse events. Thirty-one patients were treated with Hemolung Respiratory Assist System with significant improvement in pH and Pco2 in this cohort. Two patients experienced complications that prevented treatment. Of the 29 treated patients, 58% survived to 48 hours post treatment and 38% to hospital discharge. No difference in age or comorbidities were noted between survivors and nonsurvivors. There was significant improvement in pH (7.24 ± 0.12 to 7.35 ± 0.07; p < 0.0001) and Paco2 (79 ± 23 to 58 ± 14; p < 0.0001) from baseline to 24 hours. CONCLUSIONS: In this retrospective case series of 29 patients, we have demonstrated efficacy of extracorporeal Co2 removal using the Hemolung Respiratory Assist System to improve respiratory acidosis in patients with severe hypercapnic respiratory failure due to coronavirus disease 2019.