key: cord-1004211-mlvsb6w9
authors: Alharthy, Abdulrahman; Faqihi, Fahad; Memish, Ziad A; Balhamar, Abdullah; Nasim, Nasir; Shahzad, Ahmad; Tamim, Hani; Alqahtani, Saleh A; Brindley, Peter G; Karakitsos, Dimitrios
title: Continuous renal replacement therapy with the addition of CytoSorb(®) cartridge in critically ill patients with COVID‐19 plus acute kidney injury: a case‐series
date: 2020-11-15
journal: Artif Organs
DOI: 10.1111/aor.13864
sha: b8512800c740964114743d26ec34fd4ffcea16dd
doc_id: 1004211
cord_uid: mlvsb6w9

AIM: To investigate continuous renal replacement therapy (CRRT) with CytoSorb(®) cartridge for patients with life‐threatening COVID‐19 plus acute kidney injury (AKI), sepsis, acute respiratory distress syndrome (ARDS), and cytokine release syndrome (CRS). PATIENTS AND METHODS: Of 492 COVID‐19 patients admitted to our intensive care unit (ICU), 50 had AKI necessitating CRRT (10.16%) and were enrolled in the study. Upon ICU admission, all had AKI, ARDS, septic shock, and CRS. In addition to CRRT with CytoSorb(®), all received ARDS‐net ventilation, prone positioning, plus empiric ribavirin, interferon beta‐1b, antibiotics, hydrocortisone, and prophylactic anticoagulation. We retrospectively analyzed inflammatory biomarkers, oxygenation, organ function, duration of mechanical ventilation, ICU length‐of‐stay, and mortality on day‐28 post‐ICU admission. RESULTS: Patients were 49.64 ±8.90 years old (78% male) with body mass index of 26.70±2.76 kg/m(2). On ICU admission, mean Acute Physiology and Chronic Health Evaluation II, was 22.52±1.1. Sequential Organ Function Assessment (SOFA) score was 9.36±2.068 and the ratio of partial arterial pressure of oxygen to fractional inspired concentration of oxygen (PaO(2)/FiO(2)) was 117.46±36.92. Duration of mechanical ventilation was 17.38±7.39 days, ICU length‐of‐stay was 20.70±8.83 days, and mortality 28 days post‐ICU admission was 30%. Non‐survivors had higher levels of inflammatory biomarkers, and more unresolved shock, ARDS, AKI, and pulmonary emboli (8% vs. 4 %, p<0.05) compared to survivors. After 2±1 CRRT sessions with CytoSorb(®), survivors had decreased SOFA scores, lactate dehydrogenase, ferritin, D‐dimers, C‐reactive protein, and interleukin‐6; and increased PaO(2)/FiO(2) ratios, and lymphocyte counts (all p<0.05). Receiver‐operator‐curve analysis showed that post therapy values of interleukin‐6 (cutoff point > 620 pg/ml) predicted in‐hospital mortality for critically ill COVID‐19 patients (area‐under‐the‐curve: 0.87, 95% confidence‐intervals: 0.81‐0.93; p=0.001). No side effects of therapy were recorded. CONCLUSION: In this retrospective case‐series, CRRT with the CytoSorb(®) cartridge provided a safe rescue therapy in life‐threatening COVID‐19 with associated AKI, ARDS, sepsis, and hyperinflammation.

The novel coronavirus SARS-CoV-2 disease (COVID-19) has caused worldwide upheaval, and spurred unprecedented research. 1 While most patients remain asymptomatic, a portion develop critical illness, characterized by acute respiratory distress syndrome (ARDS), sepsis, multi-system organ failure (MSOF), thromboembolic disease, and associated cytokine release syndrome (CRS). [2] [3] [4] [5] Acute kidney injury (AKI) occurs in 2% to 25% of severe COVID-19 cases, and is associated with worse prognosis. [2] [3] [4] [5] [6] [7] [8] Care for patients with sepsis, ARDS, AKI and COVID-19 is largely supportive and can include continuous renal replacement therapy (CRRT). Provocatively, CRRT may also remove deleterious cytokines, such as tumor necrosis factor (TNF) α and interleukin (IL) 1β and might therefore ameliorate the underlying biochemical disorder. [9] [10] [11] [12] [13] A single-use filter, CytoSorb®, was developed to be used in addition to CRRT for patients with increased cytokines and endotoxins. [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] Experimental studies and small clinical series showed that hemadsorption with CytoSorb ® can remove up to 90% of circulating endotoxins and cytokines; however, clinical outcomes in ARDS patients are inconclusive. 24 The filter is compatible with routine extracorporeal techniques such as CRRT, hemoperfusion, hemodialysis, and extracorporeal membrane oxygenation (ECMO). To our knowledge, scarce data exist regarding the use of CytoSorb ® filters in critically-ill COVID-19 patients.

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The enormous medical, economic and societal impact of COVID-19 means that myriad therapies are being pursued, including antivirals, vaccination and convalescent plasma transfusion. [25] [26] [27] To date, none but steroids have been shown a clear benefit 28 . In a previous report, we showed that therapeutic plasma exchange might be a rescue therapy for life-threatening COVID-19 with associated CRS. 29 We build upon that experience in this retrospective case-series by examining CytoSorb ® in conjunction to CRRT for patients with severe COVID-19 and AKI.

In this retrospective case-series, we analyzed patients with life-threatening COVID-19 and associated AKI admitted to our intensive care unit (ICU) between June 1 and July 30, 2020. septic shock subsided (defined as a lactate level ≤ 2mmol/l), and iv) homeostasis achieved (i.e., the absence of electrolyte abnormalities or metabolic acidosis).

Specialized ICU staff performed the CRRT associated procedures (i.e., placement of a temporary double-lumen catheter using ultrasound, and management of the CRRT machine and solutions). We insisted upon full COVID-19 personal protective equipment, and infection control measures for respiratory, droplet and contact isolation. 43, 44 CRRT effluent was treated as biohazardous during its disposal. 45 All procedures were performed in negative-pressure isolation rooms in our

This article is protected by copyright. All rights reserved COVID-19 designated ICU.

We measured the association between the use of CytoSorb ® and levels of inflammatory inflammatory biomarkers commonly reported in COVID-19 patients: C-reactive protein (CRP), Ddimer, lactate dehydrogenase (LDH), ferritin, and interleukin-6 (IL-6). [2] [3] [4] [5] [25] [26] [27] [28] [29] CRP was defined as elevated if > 5.0 mg/L and IL-6 if > 7.0 pg/ml. 46 We measured these biochemical parameters before and after the completion of therapy. We also measured the changes in PaO 2 /FiO 2 ratio, and SOFA score before and after CytoSorb ® . The Electronic Medical Records of those COVID-19 patients who met the study's inclusion criteria were retrospectively analyzed. The available epidemiologic, clinical, and paraclinical data of the enrolled cases were stored in an electronic data bank. We analyzed days on mechanical ventilation (MV), ICU length-of-stay, and 28-day mortality post-ICU admission.

Continuous variables were expressed as mean ± standard deviation (SD) and categorical variables were expressed as absolute numbers and/or percentages. We utilized the Wilcoxon signed rank sum test for non-parametric data to compare clinical and biochemical parameters before and after CRRT, and the Fisher's exact test to compare percentages. Also, we drew Tukey boxplots, with equal whisker lengths of 1.5 interquartile ranges for both whiskers, for parameters of interest such as lymphocytes, IL-6, PaO 2 /FiO 2 ratio, and SOFA score, before and after therapy, in survivors and in non-survivors. Also, Receiver Operator curve (ROC) analysis of post therapy values of IL-6 and SOFA score for predicting in-hospital mortality was performed. All tests were two-tailed and considered statistically significant when the p value was < 0.05. Statistical analysis was performed using SPSS, version 23.0.

Of 472 COVID-19 patients admitted to the ICU during the study period, 95 patients had AKI (19.3%). Forty-five patients of these AKI patients did not require CRRT and were therefore excluded.

Fifty COVID-19 patients with AKI (10.16%) met inclusion criteria and were included in the final analysis ( Fig. 1) . SARS-CoV-2 infection was confirmed by RT-PCR performed on nasopharyngeal

This article is protected by copyright. All rights reserved swabs in all cases. The main characteristics and outcome measures of the 50 COVID-19 patients with AKI are outlined in Table 2 , and the studied biochemical parameters are presented in Table 3 . The most common symptoms of patients prior to hospital admission were cough (90%), fever (84%), and dyspnea (70%). Less common symptoms were sputum production (44%), vomiting/nausea (18%), diarrhea (14%), altered level of consciousness (8%), and anosmia (6%). Eleven of 50 patients (22%) acquired SARS-CoV-2 infection in areas where several other cases were simultaneously discovered (i.e., residential area, or shopping mall) and were therefore deemed a cluster infection. days, and mortality on day-28 post-ICU admission was 30% (Table 2) .

Upon ICU admission, all COVID-19 patients with AKI had anuria and metabolic derangement (i.e., metabolic acidosis, and electrolyte abnormalities), ARDS, septic shock, and CRS ( Table 4 illustrates the main studied parameters before and after CRRT completion. The 15 nonsurvivors had refractory ARDS, unresolved septic shock with increased norepinephrine requirements, and coagulopathy; characterized by increased international normalization ratio but relatively preserved platelet counts (Table 4 ). [2] [3] [4] [5] [6] Platelet counts were reduced post-CRRT but no clinical significance was observed. Non-survivors had persistently abnormal renal function and lymphocytopenia, plus increased CRP, LDH, ferritin, and especially high levels of IL-6, post-therapy (Table 4 , Fig. 2 ). All non-survivors expired approximately within two weeks post-ICU admission (10±4 days), (Fig.3) For the 35 survivors, and after 2±1 sessions of CVVHD with CytoSorb ® , diuresis could be initiated, vasopressors were weaned off, and renal function gradually improved. Survivors also had significantly increased PaO 2 /FiO 2 ratio. Survivors had decreases in SOFA score, lactate dehydrogenase, ferritin, D-dimers, C-reactive protein, lactate, and interleukin-6. Survivors also had persistent increases in lymphocyte counts post-CRRT plus CytoSorb ® ( (Fig.5 ).

Survivors were successfully liberated from the mechanical ventilation, and discharged from the hospital to home isolation 32 ± 12 days post-ICU admission. SARS-CoV-2 RNA, assayed by RT-PCR and microbiology were negative in survivors after 22 ± 4 days post-ICU admission.

In this retrospective case-series, we showed that CRRT in conjunction with CytoSorb ® was associated with reduced inflammatory biomarkers, improved oxygenation and better renal function in a subset of patients with life-threatening COVID-19. Approximately 70% responded favorably and survived. In contrast, non-responders (30%) continued on a fulminant clinical course, characterized by high inflammatory biomarkers, lymphocytopenia, refractory ARDS, recalcitrant shock, and progressed towards MSOF and death. [1] [2] [3] [4] [5] Our pre-intervention incidence of AKI was 19.1%, while 10.16% of our critically-ill COVID-19 met criteria for CRRT. 1-8, 48,49 The mortality rate in patients with life-threatening COVID-19 and AKI (30%) was comparable, or lower, than previous studies, which reported mortality rates up to 52%. [1] [2] [3] [4] [5] [6] [7] [8] 48, 49, 50 Our work also supplements the nascent evidence base supporting CRRT plus CytoSorb ® in COVID-19 patients with AKI. Previous studies suggested a putative benefit in patients with septic shock but failed to show any significant mortality effect. 24, 51 Notably, our 50 patients had lifethreatening disease, as highlighted by multiple poor prognosticators: AKI, ARDS, and hyperinflammation [1] [2] [3] [4] [5] [6] [7] [8] [29] [30] [31] [32] [33] [34] [35] [36] This made it comparatively easy to justify this putative rescue therapy. Our work also bolsters the presumed link between continued biochemical derangement and COVID-19

death. Our non-survivors not only had persistent elevation in inflammatory biomarkers, they had lymphocytopenia, unresolved septic shock, refractory ARDS and higher PE prevalence compared to survivors/responders. Our pilot work is encouraging, but larger prospective studies are needed before

This article is protected by copyright. All rights reserved claiming this therapy is clinically warranted, given that our feasibility study was underpowered and retrospective (see additional limitations below). Regardless, it does help build the case for that future work.

The RECOVERY trial showed that early suppression of inflammation using low-dose dexamethasone was beneficial in COVID-19. 28 CytoSorb ® therapy could also mitigate hyperinflammation in life-threatening COVID-19. In future work we intend to further explore this by comparing CRRT as a stand-alone therapy versus CRRT with CytoSorb ® . The gradual resolution of renal function in our patients also supports, though does not confirm, the possibility that acute tubular necrosis is part of COVID-19 associated renal dysfunction. 48, [49] [50] [51] [52] Other possibilities include hemodynamic instability, prerenal injury, and even glomerulopathy and glomerulonephritis. [1] [2] [3] [4] [5] [6] [7] [8] [49] [50] [51] [52] [53] [54] [55] [56] Future research could also focus on patients who did not respond to therapy. In addition to increased IL-6, our work suggests that this may be linked to increased PE prevalence. The current results support that COVID-19 is associated with an increased incidence of thromboembolic disease and that this portends a bad prognosis. [57] [58] [59] [60] In future work, we intend to measure levels of ADAMTS 13 activity, a marker of thromboinflammation, and a prognosticator in MSOF. [60] [61] [62] After all, extracorporeal blood purification therapy may ultimately be insufficient to rapidly counteract severe thromboinflammation during its late stages.

This case-series has limitations, which reduce its generalizability. In addition to its retrospective nature, there is always the possibility that our patients might have improved without our intervention, or because of the other empiric treatments. In other words, a detailed subgroup analysis was not possible due to the small sample size. Previously, it was suggested that continuous hemoadsorption with CytoSorb ® can remove circulating antibiotics. 63 Also, scarce data exist regarding the effect of extracorporeal blood purification therapies on the levels of antiviral agents. Regrettably, we did not have the capability to measure antibiotics/antivirals levels, additional cytokines or procalcitonin levels. A pilot study showed positive effects on lactate and procalcitonin levels following CytoSorb ® therapy. 64 We confirmed the positive effect on lactate levels but not on procalcitonin.

This article is protected by copyright. All rights reserved However, IL-6 signaling is mediated by a distinctive IL-6 receptor system, which may also play a physiologic role in immune-inflammatory disorders. 70 

This article is protected by copyright. All rights reserved AKI. Conceivably, the addition of hemoadsorption to CRRT or ECMO may expand their potential application in critically ill COVID-19 patients.

In this retrospective case-series, we showed that the combination of CRRT and CytoSorb ® is a safe potential rescue therapy in critically ill COVID-19 patients with AKI, ARDS, septic shock, and hyperinflammation. The majority of critically ill COVID-19 patients who underwent CRRT with CytoSorb ® survived (70%); while non-responders/non-survivors (30%) had increased prevalence of PE and progressed to MSOF. Future larger prospective studies are required to confirm or refute these encouraging, albeit initial, findings.

CRRT= continuous renal replacement therapy, ICU: intensive care unit, ARDS: acute respiratory distress syndrome, MSOF: multi-system organ failure, CRS: cytokine release syndrome, COVID-19:

SARS-CoV-2 disease, CRP: C-reactive protein, LDH: lactate dehydrogenase, IL-6: interleukin-6, RT-PCR: Real-Time-Polymerase-Chain-Reaction, PaO 2 /FiO 2 ratio: partial arterial pressure of oxygen to fractional inspired concentration of oxygen ratio, PE: pulmonary embolism, DIC: disseminated intravascular coagulation, RIFLE criteria: "risk", "injury" and "failure" criteria, APACHE II score:

Acute Physiology and Chronic Health Evaluation II score, SOFA score: Sequential Organ Function Assessment score; ECMO = veno-venous extracorporeal membrane oxygenation; ROC = Receiver operator curve.

All authors contributed to data acquisition, analysis, and interpretation. All authors reviewed and approved the final version of the manuscript and agree with its submission to the journal. 

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All authors declare no conflicts of interest.

No financial support was received for this study.

Genomic characterization and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

China Medical Treatment Expert Group for Covid-19 Clinical Characteristics of Coronavirus Disease 2019 in China

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in

China: a retrospective cohort study

COVID-19 Lombardy ICU Network. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region

Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 (COVID-19) in Wuhan, China: a retrospective study

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirusinfected pneumonia in Wuhan

A prospective, longitudinal evaluation of point-of-care lung ultrasound in critically ill patients with severe COVID-19 pneumonia

Levy Accepted Article This article is protected by copyright. All rights reserved MM, Artigas A, Phillips GS, et al. Outcomes of the Surviving Sepsis Campaign in intensive care units in the USA and Europe: a prospective cohort study

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)

Continuous veno-venous hemofiltration with dialysis removes cytokines from the circulation of septic patients

Clinical review: blood purification for sepsis

Removal of mediators by continuous hemofiltration in septic patients

Continuous hemoadsorption with a cytokine adsorber during sepsis -a review of the literature

Broad adsorption of sepsis-related PAMP and DAMP molecules, mycotoxins, and cytokines from whole blood using CytoSorb(R) sorbent porous polymer beads

The effect of a novel extracorporeal cytokine hemoadsorption device on IL-6 elimination in septic patients: a randomized controlled trial

In vitro comparison of the adsorption of inflammatory mediators by blood purification devices

Effects of hemoadsorption on cytokine removal and short-term survival in septic rats

Evaluation of the Cytosorb hemoadsorptive column in a pig model of severe smoke and burn injury

Use of a novel hemoadsorption device for cytokine removal as adjuvant therapy in a patient with septic shock with multi-organ dysfunction: a case study

Septic shock secondary to betahemolytic streptococcus-induced necrotizing fasciitis treated with a novel cytokine adsorption therapy

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

First successful combination of ECMO with cytokine removal therapy in cardiogenic septic shock: a case report

CytoSorb, a novel therapeutic approach for patients with septic shock: a case report

International registry on the use of the CytoSorb(R) adsorber in ICU patients: study protocol and preliminary results

Compassionate Use of Remdesivir for Patients with Severe Covid-19

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19

Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial

Dexamethasone in Hospitalized Patients with Covid-19 -Preliminary Report

Therapeutic plasma exchange in adult critically ill patients with life-threatening SARS-CoV-2 disease: a pilot study

Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)

KDIGO clinical practice guideline for acute kidney injury

Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries

The Berlin definition of ARDS: an expanded rationale, justification, and supplementary material

ICU severity of illness scores: APACHE, SAPS and MPM

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016

The Surviving Sepsis Campaign Bundle: 2018 update

Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19

Cytokine release syndrome in severe COVID-19

Detection of SARS-CoV-2 in different types of clinical specimens

Improved Molecular Diagnosis of COVID-19 by the Novel, Highly Sensitive and Specific COVID-19-RdRp/Hel Real-Time Reverse Transcription-PCR Assay Validated In Vitro and with Clinical Specimens

World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects

Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Guideline Update Implementation: Asia Summit Conference Report

infectionprevention-and-control-during-health-care-when-novel-coronavirus-(ncov)-infection-is-suspected-20200125

Air, surface, environmental, and personal protective equipment contamination by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from a symptomatic patient

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Saudi Ministry of Health

Acute kidney injury in patients hospitalized with COVID-19

Renal involvement and early prognosis in patients with COVID-19 pneumonia

Outcomes for Patients With COVID-19 and Acute Kidney Injury: A Systematic Review and Meta-Analysis

Hemoadsorption with CytoSorb shows a decreased observed versus expected 28-day all-cause mortality in ICU patients with septic shock: a propensityscore-weighted retrospective study. Crit Care

COVID-19 and kidney failure in the acute care setting: our experience from Seattle

Collapsing glomerulopathy in a patient with coronavirus disease 2019 (COVID-19)

Collapsing glomerulopathy in a COVID-19 patient

Acute kidney injury due to collapsing glomerulopathy following COVID-19 infection

Tubuloreticular inclusions in COVID-19-related collapsing glomerulopathy

Association of treatment dose anticoagulation with in-Hospital Accepted Article This article is protected by copyright. All rights reserved survival among hospitalized patients with COVID-19

Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy

Incidence of thrombotic complications in critically ill ICU patients with COVID-19

Effect of therapeutic plasma exchange on endothelial activation and coagulation-related parameters in septic shock

ADAMTS-13 in critically Ill patients with septic syndromes and noninfectious systemic inflammatory response syndrome

Effect of renal clearance and continuous renal replacement therapy on appropriateness of recommended meropenem dosing regimens in critically ill patients with susceptible life-threatening infections

Extracorporeal cytokine adsorption in septic shock: a proof of concept randomized, controlled pilot study

Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19

The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality

Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)?

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

The association of interleukin-6 value, interleukin inhibitors, and outcomes of patients with COVID-19 in New York City

Cloning and expression of the human interleukin

Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130

Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease

Positive RT-PCR Test Results in Patients Recovered From COVID-19

SARS-CoV-2 viral load in upper respiratory specimens of infected patients

Recurrent Positive Reverse Transcriptase-Polymerase Chain Reaction Results for Coronavirus Disease 2019 in Patients Discharged From a Hospital in China

Effect of Targeted Polymyxin B Hemoperfusion on 28-Day Mortality in Patients With Septic Shock and Elevated Endotoxin Level: The EUPHRATES Randomized Clinical Trial

Polymyxin B hemoperfusion in endotoxemic septic shock patients without extreme endotoxemia: a post hoc analysis of the EUPHRATES trial

Early isovolaemic haemofiltration in oliguric patients with septic shock

Coupled plasma filtration adsorption

Ferritin (ng/ml

D-dimers (mcg/ml, normal: < 1) 3.18 ± 2

We acknowledge all health care workers involved in the diagnosis and treatment of COVID-19 patients worldwide.

 Table 4 . Comparison of parameters before and after the completion of continuous renal replacement therapy with CytoSorb ® in COVID-19 patients with acute kidney injury who survived (n=35), and did not survive (n=15). 

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