key: cord-0729917-w8rshoe5
authors: Allescher, Julia; Rasch, Sebastian; Wiessner, Johannes R.; Perez Ruiz de Garibay, Aritz; Huberle, Christina; Hesse, Felix; Schulz, Dominik; Schmid, Roland M.; Huber, Wolfgang; Lahmer, Tobias
title: Extracorporeal carbon dioxide Removal (ECCO(2)R) with the Advanced Organ Support (ADVOS) system in critically ill COVID‐19 patients
date: 2021-07-26
journal: Artif Organs
DOI: 10.1111/aor.14044
sha: 7247a65022fb4d46e2a39bee0f7ec97ecb442956
doc_id: 729917
cord_uid: w8rshoe5

INTRODUCTION: Disturbed oxygenation is foremost the leading clinical presentation in COVID ‐19 patients. However, a small proportion also develop carbon dioxide removal problems. The Advanced Organ Support (ADVOS) therapy (ADVITOS GmbH, Munich, Germany) uses a less invasive approach by combining extracorporeal CO(2)‐removal and multiple organ support for the liver and the kidneys in a single hemodialysis device. The aim of our study is to evaluate the ADVOS system as treatment option in predominantly old‐age‐COVID‐19 patients with multi‐organ failure and carbon dioxide removal problems. MATERIAL AND METHODS: COVID‐19 patients suffering from severe respiratory insufficiency, receiving at least two treatments with the ADVOS multi system (ADVITOS GmbH, Munich, Germany), were eligible for study inclusion. Briefly, these included patients with acute kidney injury (AKI) according to KDIGO guidelines, and moderate or severe ARDS according to the Berlin definition, who were on invasive mechanical ventilation for more than 72 hours. RESULTS: In total, nine COVID‐19 patients (137 ADVOS treatment sessions with a median of 10 treatments per patient) with moderate to severe ARDS and carbon dioxide removal problems were analyzed. During the ADVOS treatments, a rapid correction of acid‐base balance and a continuous CO(2) removal could be observed. We observed a median continuous CO(2) removal of 49.2 ml/min (IQR: 26.9 – 72.3 ml/min) with some treatments achieving up to 160 ml/min. The CO(2) removal significantly correlated with blood flow (Pearson 0.421; p < 0.001), PaCO(2) (0.341, p < 0.001) and HCO(3) (‐) levels (0.568, p < 0.001) at the start of the treatment. The continuous treatment led to a significant reduction in PaCO(2) from baseline to the last ADVOS treatment CONCLUSION: In conclusion, it was feasible to remove CO(2) using the ADVOS system in our cohort of COVID‐19 patients with acute respiratory distress syndrome and multiorgan failure. This efficient removal of CO(2) was achieved at low blow flows up to 300 ml/min using a conventional hemodialysis catheter and without a membrane lung or a gas phase.

Since the outbreak of the COVID-19 pandemic, most patients present with either none or mild symptoms. However, up to 15% of COVID-19 patients need hospitalization and nearly 5% need intensive care unit (ICU) support including mechanical ventilation and, in few cases, further extracorporeal organ support [1, 2] . Based on a hyperactive "cytokine storm", an uncontrolled systemic inflammatory state leads to an acute respiratory failure and in 14% of all cases, acute respiratory distress syndrome (ARDS) with an impairment of gas exchange for both oxygen and carbon dioxide (CO 2 ) [3] [4] [5] [6] . Disturbed oxygenation is foremost the leading clinical presentation in COVID -19 patients. However, a small proportion also develop carbon dioxide removal problems [7] .

In order to avoid ventilator induced lung injury (VILI), lung-protective ventilation with low tidal volume and low driving pressure using extracorporeal carbon dioxide removal systems are emerging in a potential respiratory support strategy [8] [9] [10] . ECCO 2 R uses medium to low blood flows of up to 500 ml/h [11] . In contrast to ECMO, ECCO 2 R is less invasive and requires lower blood flows. High invasiveness and high blood flows may be a limiting factor particularly in elderly patients and those with multiple comorbidities [12, 13] . Systems operating at lower blood flows such as ECCO 2 R, working either alone or in combination with renal replacement therapy (RRT) have already shown feasibility in COVID-19 patients with ARDS [14] .

Nevertheless, this approach is not exempt of side effects, as shown in larger studies [15] [16] [17] .

However, the possibility of ECCO 2 R improving the outcome of affected COVID-19 patients has yet to be shown in larger studies.

The Advanced Organ Support (ADVOS) therapy (ADVITOS GmbH, Munich, Germany) uses a less invasive approach by combining extracorporeal CO 2 -removal and multiple organ support for the liver and the kidneys in a single hemodialysis device. The low invasiveness of this system combined with the possibility of fluid-based CO 2 removal and acid-base balance correction may be a promising approach for COVID-19-associated ARDS patients with multiple comorbidities [18] [19] [20] [21] .

This article is protected by copyright. All rights reserved The aim of our study is to evaluate the ADVOS system as treatment option in predominantly old-age-COVID-19 patients with multi-organ failure and carbon dioxide removal problems.

This observational cohort study was conducted at a tertiary care ICU (department of internal medicine) of the University Hospital of Technical University of Munich, Germany. Patients (18 years of age or older) with confirmed severe COVID-19 pneumonia (clinical signs, typical laboratory constellation, PCR test for SARS-CoV-2 positive and chest computed tomography (CT) scan with typical signs) who were admitted to the ICU due to acute respiratory failure were eligible for study inclusion. The study was approved by the institutional review board of the Technical University of Munich, Germany (178/20S). Written informed consent was obtained by the patient or their legal representatives.

COVID-19 patients suffering from severe respiratory insufficiency, receiving at least two treatments with the ADVOS multi system (ADVITOS GmbH, Munich, Germany), were eligible for study inclusion. Briefly, these included patients with acute kidney injury (AKI) according to KDIGO guidelines [22] , and moderate or severe ARDS according to the Berlin definition [23] , who were on invasive mechanical ventilation for more than 72 hours. Patients without informed consent, pregnant patients, as well as patients under 18 years of age were excluded.

The ADVOS multi system is an albumin hemodialysis system which operates with conventional dialysis catheters with blood flows between 100-400 ml/min. The system has been described and characterized in previous publications [18 -20] . Briefly, three circuits (the extracorporeal circuit, the dialysate circuit and the ADVOS multi circuit) allow water-soluble and protein-bound toxins removal and acid-base balance correction ( Figure 1 ). In the extracorporeal circuit, toxins diffuse through a semipermeable high-flux membrane into the dialysate circuit. For an enhanced protein-bound toxins removal, albumin is added into the dialysate, which is continuously regenerated by pH and temperature changes in the ADVOS multi circuit. This modifiable dialysate additionally enables an acid-base balance correction and a fluid-based CO 2 removal through the correction and, if needed, removal of H + and HCO 3 -, as described in detail in the discussion [20] . Citrate anticoagulation was used in all patients during the treatment.

Routinely assessed laboratory parameters including creatine, blood urea nitrogen (BUN), C-reactive protein (CRP), procalcitonin, bilirubin, calcium, albumin, INR, activated thromboplastin time,

This article is protected by copyright. All rights reserved leucocytes, platelets, hemoglobin, and blood gas analysis were documented. Additionally, ventilation parameters including tidal volume, minute ventilation, respiratory rate, positive expiratory pressure, peak pressure, fraction of inspired oxygen (FiO 2 ), positive inspiratory pressure, and oxygen saturation were assessed. Finally, clinical data on pre-existing illnesses, catecholamine doses, and ADVOS treatment parameters were documented using a clinical information system. For the analysis, available parameters immediately before and immediately after each ADVOS session were analyzed. To quantify the removal capacity blood gas analysis at the inlet and the outlet of the dialyzers were performed. The following equation was used for the calculation of CO 2 removal in ml/min [20, 24] :

In this equation, ∆HCO3-and ∆pCO2 represent the difference between the inlet and the outlet of the dialyzer for HCO 3 and pCO 2 in mmol/l and mmHg, respectively; K S is the solubility constant for CO 2 in blood (0.03 mmol/l/mmHg); Q b is the corresponding blood flow in l/min at the time of the blood analysis; and V m is the molar volume of CO 2 at STP (22.4 ml/mmol).

Patients were followed up until hospital discharge or until death.

Variables were reported as median and 25%-75% interquartile range (IQR), if not stated otherwise.

The Student t test for paired samples was used to compare values before and after ADVOS sessions 

In total, nine COVID-19 patients with moderate to severe ARDS and carbon dioxide removal problems were analyzed. Patients' characteristics and individual case reports at baseline (immediately before the first ADVOS session) are presented in Table 1 and Supplementary Table 1 , respectively.

In total, 137 ADVOS treatment sessions with a median of 10 treatments per patient (IQR: 8-20 treatments) and a median duration of 22 hours (IQR: 15-24 hours) were performed ( Table 2) . A median blood flow of 300 ml/min (IQR: 250-300 ml/min) and a median dialysate pH setting of 8.6

(IQR: 8.4-8.8) was employed. Regional citrate anticoagulation was applied in all sessions, either alone (8%) or in combination with unfractionated heparin (92%). Details on ADVOS settings and anticoagulation rates can be found in Table 2 .

During the ADVOS treatments, a rapid correction of acid-base balance and a continuous CO 2 removal could be observed. A significant removal of water-soluble substances (i.e., creatinine 1.5 vs. 0.8 mg/dl, p = 0.01 and BUN 30 vs. 11 mg/dl, p = 0.003), a significant improvement in blood pH (7.26 vs. 7.41, p = 0.003), serum bicarbonate and base excess were achieved after the first ADVOS treatment (Table 3) . Changes for blood pH are shown in Figure 2a .

We observed a median continuous CO 2 removal of 49. Table 4 . The respiratory acidosis could be shifted towards physiological values via the removal of CO 2 . No significant changes were observed in ventilation parameters. The in-hospital mortality in our cohort was 55% and the median ICU-length of stay was 24 days (IQR: 18 -50 days).

The results of our study demonstrate the feasibility of the ADVOS multi albumin hemodialysis device removal, demonstrating that it is an effective way to mobilize CO 2 stores in the body and that the relative change of PaCO 2 is related to the amount of CO 2 stores mobilized [26] . These findings are consistent with previous in vitro data with the ADVOS system removing up to 25% of the body's normal CO 2 (assuming the amount of CO 2 produced by a healthy adult human is 210 ml/min) [20, 27] .

This article is protected by copyright. All rights reserved Beside these in vitro experiments it is well known that severe hypercapnia affects the function of extrapulmonary organs including the brain and the cardiovascular system in a negative manner [28] .

Moreover, hypercapnic acidosis is described to increase pulmonary vasoconstriction and furthermore increases the right ventricular afterload [29] . Beyond these side-effects of hypercapnia the main approach to decrease elevated carbon dioxide levels is to avoid ventilator induced lung injury as a consequence of an inhomogeneous lung overdistension [30] .

Pilot studies suggest that CO 2 removal at lower blood flows than ECMO is feasible to facilitate an ultraprotective ventilation in a less invasive way and limit ventilator-induced lung injury in ARDS patients [15, 16] . However, effects of ECCO 2 R are limited and a combination with other devices is needed to provide multiple organ support in a substantial proportion of critically ill patients.

In contrast to other ECCO 2 R devices using a pressure gradient between blood and a gas phase, the of metabolic acidosis. This basic chemical principle, which is also physiologically employed by the kidney for acidosis compensation [31,32], is the proposed mechanism for CO 2 removal and acid-base balance correction during ADVOS treatments, as described in detail elsewhere [20, 33] .

The efficiency of the process was correlated with three major aspects, which had been underlined in previous in vitro analyses [20] : Firstly, the starting CO 2 levels (high levels of CO 2 resulted in a higher removal).Secondly, the dialysate pH setting (the CO 2 removal is more effective with a dialysate pH > 8.5) and thirdly, the blood flow (the higher the blood flow the higher the removal).

In contrast to the CO 2 removal devices combined with a renal replacement therapy device, ADVOS provides a combined support for kidney, liver, lung and acid-base balance correction in a single device using a conventional dialysis catheter. In the device patients' blood interacts with the albumin dialysate while a direct contact to a gas phase is avoided; thus, reducing the probability of adverse events. Moreover, our data on CO 2 elimination are accompanied by a concomitant removal and significant reduction of creatinine or urea, as previously shown by others [18, 19, 21, 34] .

This article is protected by copyright. All rights reserved 

In conclusion, it was feasible to remove CO 2 using the ADVOS system in our cohort of COVID-19 patients with acute respiratory distress syndrome and multiorgan failure. This efficient removal of CO 2 was achieved at low blow flows up to 300 ml/min using a conventional hemodialysis catheter and without a membrane lung or a gas phase. In addition, acid-base balance correction and creatinine and BUN levels decrease were achieved already within the first treatment. Further studies are needed to demonstrate whether the effects of the ADVOS therapy and those of carbon dioxide removal can help to reduce the burden of mechanical ventilation by either reducing the time of ventilation or favoring an ultraprotective ventilation.

This article is protected by copyright. All rights reserved Tables   Table 1 presents 

This article is protected by copyright. All rights reserved 

Management of COVID-19 Respiratory Distress

Extracorporeal Blood Purification and Organ Support in the Critically Ill Patient during COVID-19 Pandemic: Expert Review and Recommendation

Is a "Cytokine Storm" Relevant to COVID-19?

Respiratory mechanics and gas exchanges in the early course of COVID-19 ARDS: A hypothesis-generating study

Acute complications and mortality in hospitalized patients with coronavirus disease 2019: A systematic review and meta-analysis

Position Paper for the State of the Art Application of Respiratory Support in Patients with COVID-19 -German Respiratory Society

Acute Respiratory Distress Syndrome: Advances in Diagnosis and Treatment

Ventilation management and clinical outcomes in invasively ventilated patients with COVID-19 (PRoVENT-COVID): A national, multicentre, observational cohort study

Options in extracorporeal support of multiple organ failure

Accepted Article This article is protected by copyright. All rights reserved

Respiratory and metabolic acidosis correction with the ADVanced Organ Support system

Registry on extracorporeal multiple organ support with the advanced organ support (ADVOS) system: 2-year interim analysis

Kidney Disease Improving Global Outcomes KDIGO Acute Kidney, Injury Work Group. KDIGO clinical practice guideline for acute kidney injury

Acute respiratory distress syndrome: the Berlin Definition

Extracorporeal CO2 removal by hemodialysis: in vitro model and feasibility

Low-flow CO2 removal in combination with renal replacement therapy effectively reduces ventilation requirements in hypercapnic patients: A pilot study

Mobilizing Carbon Dioxide Stores. An Experimental Study

Treatment of acute respiratory failure by extracorporeal carbon dioxide elimination performed with a surface heparinized artificial lung

Combined lung injury, meningitis and cerebral edema: How permissive can hypercapnia be?

and HCO 3 -between the inlet and the outlet of the dialyzer during ADVOS treatments. Overall complete data sets from 128 treatments were available

= 128) Post-dialyzer (n = 128) median (IQR 25%-75%) median (IQR 25%-75%)

Accepted Article