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      Early Hemoperfusion for Cytokine Removal May Contribute to Prevention of Intubation in Patients Infected with COVID-19

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          Hemoperfusion (HP) was helpful to prevent the development and progression of acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), liver failure, and septic shock by removing cytokines and other inflammatory mediators and ultimately preventing progression toward multiple organ failure. A 54-year-old man diagnosed with COVID-19 was hospitalized in the intensive care unit. The patient's O<sub>2</sub> saturation was 80% using an oxygen mask, which was gradually declining. After 4 sessions of HP/continuous renal replacement therapies (CRRT), O<sub>2</sub> saturation reached to 95%, and the patient was transferred to the general ward. Performing HP/CRRT at the early stages of ARDS can obviate the need for intubating patients with COVID-19. Punctual and early use of HP and CRRT in the treatment of ARDS in patients with COVID-19 prevented the progression of ARDS and patient intubation, reduced respiratory distress and the patient's dependence on oxygen, prevented other complications such as AKI and septic shock in the patient, and reduced mortality and hospital length of stay.

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          Care for Critically Ill Patients With COVID-19

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            Treatment for severe acute respiratory distress syndrome from COVID-19

            In The Lancet Respiratory Medicine, Kollengode Ramanathan and colleagues 1 provide excellent recommendations for the use of extracorporeal membrane oxygenation (ECMO) for patients with respiratory failure from acute respiratory distress syndrome (ARDS) secondary to coronavirus disease 2019 (COVID-19). The authors describe pragmatic approaches to the challenges of delivering ECMO to patients with COVID-19, including training health-care personnel, resolving equipment and facilities issues, implementing systems for infection control and personal protection, providing overall support for health-care staff, and mitigating ethical issues. They also address some of the anticipated challenges with local and regional surges in COVID-19 ARDS cases; although there has been an increase in hospitals with the capacity to provide ECMO, the potential demand might exceed the available resources. Furthermore, some health-care systems offer advanced therapies such as ECMO but lack a coordinated local, regional, or national referral protocol. Given the practical constraints on substantially increasing the global availability of ECMO services in the next few months, it is important to emphasise the other evidence-based treatment options that can be provided for patients with severe ARDS from COVID-19 (figure ). 2 Before endotracheal intubation, it is important to consider a trial of high-flow nasal oxygen for patients with moderately severe hypoxaemia. This procedure might avoid the need for intubation and mechanical ventilation because it provides high concentrations of humidified oxygen, low levels of positive end-expiratory pressure, and can facilitate the elimination of carbon dioxide. 4 WHO guidelines support the use of high-flow nasal oxygen in some patients, but they urge close monitoring for clinical deterioration that could result in the need for emergent intubations because such procedures might increase the risk of infection to health-care workers. 5 Figure Therapeutic options for severe acute respiratory distress syndrome related to coronavirus disease 2019 ppm=parts per million. For patients with COVID-19 who require endotracheal intubation, use of low tidal volume (6 mL/kg per predicted bodyweight) with a plateau airway pressure of less than 30 cm H2O, and increasing the respiratory rate to 35 breaths per min as needed, is the mainstay of lung-protective ventilation. If the hypoxaemia progresses to a PaO2:FiO2 ratio of less than 100–150 mm Hg, there are several therapeutic options. The level of positive end-expiratory pressure can be increased by 2–3 cm H2O every 15–30 min to improve oxygen saturation to 88–90%, with the goal of maintaining a plateau airway pressure of less than 30 cm H2O. Lower driving pressures (plateau airway pressure minus positive end-expiratory pressure) with a target of 13–15 cm H2O can also be used. If the patient is not responding to adjustment of the level of positive end-expiratory pressure, additional strategies might stabilise them. Recruitment manoeuvres probably have little value, 6 but moderate pressures of approximately 30 cm H2O for 20–30 s can be applied in the presence of a physician to monitor haemodynamics. If there is no improvement in oxygenation or driving pressure, or if the patient develops hypotension or barotrauma, the recruitment manoeuvres should be discontinued. If there is considerable dyssynchrony with positive pressure ventilation, accompanied by increased plateau airway pressures and refractory hypoxaemia, then deep sedation should be used followed by prompt institution of neuromuscular blockade with cisatracurium. Additionally, prone positioning should be instituted, unless there is a specific contraindication, and can be initiated along with the interventions already described. For persistent refractory hypoxaemia even with prone positioning, neuromuscular blockade, and efforts to optimise positive end-expiratory pressure therapy, there are additional options. Inhaled 5–20 ppm NO might improve oxygenation. Insertion of an oesophageal balloon to measure transpulmonary pressures to set an optimal positive end-expiratory pressure can be considered in patients with moderate-to-severe obesity, although a 2019 trial in patients with ARDS did not show the benefit of this procedure in most patients. 7 Fluid management is important to consider as a measure to reduce pulmonary oedema. 8 In the absence of shock, fluid conservative therapy is recommended to achieve a negative fluid balance of 0·5 to 1·0 L per day. In the presence of shock, fluid balance might be achieved with renal replacement therapy, especially if there is associated acute kidney injury and oliguria. Antibiotics should be considered since secondary bacterial infections have been reported in patients with COVID-19. 9 Glucocorticoids should be avoided in view of the evidence that they can be harmful in cases of viral pneumonia and ARDS from influenza. 10 Rescue therapy with high-dose vitamin C can also be considered. 11 Finally, ECMO should be considered using the inclusion and exclusion criteria of the EOLIA trial. 3 Since treatment of severe ARDS from COVID-19 is an ongoing challenge, it is important to learn from the patients who have been treated to gain an understanding of the disease's epidemiology, biological mechanisms, and the effects of new pharmacological interventions. Currently, there are some research groups working to coordinate and disseminate key information, including information on patients who have been treated with ECMO for COVID-19, although an accurate estimate of the number of such patients is not currently available. The Extracorporeal Life Support Organization is an international non-profit consortium that plans to maintain a registry of patients to facilitate an improved understanding of how ECMO is being used for patients with COVID-19.
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              Coronavirus Epidemic and Extracorporeal Therapies in Intensive Care: si vis pacem para bellum

              The worldwide outbreak of coronavirus disease 2019 (COVID-19) has demonstrated that we are all part of a small world where diffusion of contagious diseases is inevitable [1]. Although the new coronavirus originated in Wuhan seems to present lower lethality compared to previous epidemic outbreaks from other coronaviruses, its capacity of diffusion has been phenomenal [2, 3]. One infected individual may transmit the virus to 2 or 3 others [4]. Of note, screening based on symptoms and signs is ineffective and asymptomatic persons can spread the disease [5]. In the very early phases, before this wide diffusion of the virus, a call to action was published in Lancet Respiratory Medicine [6] underlining the need of alertness for zoonotic virus infections crossing species and infecting human populations [7]. In particular, recommendation was made to prepare intensive care teams to deliver extracorporeal organ support (ECOS) therapies in infected patients whose pulmonary syndromes are particularly severe [8]. Once again, despite previous experiences presented higher incidence of severe complications and lethality, the current outbreak still requires intensive care for 5% of the infected population. Among those critically ill patients, the mortality rate is 49%. Even with the specific tropism for airway epithelial cells, the infection seems to be weak in humans and transmission is likely to occur only when lower respiratory tract disease develops. COVID-19 causes mild flu-like symptoms or even no symptoms in the majority of the patients [3]. Coronaviruses bind to receptors such as angiotensin-converting enzyme 2. Angiotensin-converting enzyme 2 is present in the epithelia of the lung, small intestine, colon, and biliary tract. In fact, viral nucleic acids were found in stools and anal swabs of patients diagnosed with COVID-19 infection [9]. In a cohort of COVID-19-infected patients from Singapore, half (4 out of 8) of patients tested had the virus detected in stools [10]. This might explain liver dysfunction, diarrhea, nausea, and vomiting that occurred in patients with pneumonia, namely, the gut-lung crosstalk [8, 11]. In a Chinese group of patients with pneumonia caused by COVID-19, 23% were admitted to intensive care unit (ICU), 17% had acute respiratory distress syndrome, and 11% died [11]. Major preventive measures have been undertaken in specific areas where the incidence was significantly higher, to limit the diffusion of the virus [7]. Despite those measures, the requirement of ICU services and stations still has dramatically increased. Personal communications and early reports mostly coming from China suggest that 67% of severely ill COVID-19 patients may present with additional organ dysfunction syndromes [8, 11, 12]. This has been, at least in part, related to a sepsis-like syndrome induced by high level of circulating cytokines [2, 12]. In such circumstances, while pulmonary exchanges are compromised and dominate the clinical scenario, acute kidney injury and heart and liver dysfunction may also become evident [8, 12, 13, 14]. Cytokine storm may be induced by a superimposed septic syndrome or by the direct effect of the virus on the infected host. In the past, the experience matured with H1N1 influenza, SARS, and MERS has suggested that the severity of illness depended on comorbidities and the immune-competence of the individual. In severe situations, however, an uncontrolled inflammatory state or a subsequent/simultaneous immune-paralysis is the direct consequence of endocrine effects of pro- and anti-inflammatory cytokines spilled over into the systemic circulation. Of special interest, in a retrospective analysis of a German cohort [15] of 25 critically ill H1N1-infected patients, the prevalence of virus-associated hemophagocytic syndrome (VAHS) was 36%. All patients with the syndrome had received extracorporeal membrane oxygenation (ECMO). ECMO could have been a trigger or an amplifier of cytokine activation. The pathogenesis of VAHS involves excessive production of interferon gamma and interleukin-2 [16]. VAHS itself is a prototype of a cytokine storm syndrome. In our present experience in San Bortolo Hospital, all our 4 COVID-19 critically ill patients have hyperferritinemia, raising awareness of VAHS as a differential diagnosis. In organ dysfunction syndromes when pharmacological treatment is simply not available or efficacious, mechanical ventilation and hemodynamic support seem to be the only possible therapeutic strategy [17]. However, extracorporeal therapies such as hemofiltration or hemoperfusion (HP) offer a new possibility to support different organs in a multiple organ dysfunction condition. Using specific extracorporeal circuits and devices, heart, lungs, kidneys, and liver can be partially replaced or at least sustained during the severe phase of the syndrome. The concept is known as ECOS [18, 19, 20]. The most important technique in these cases is the ECMO mostly applied in veno-venous mode [21, 22, 23]. Furthermore, extracorporeal CO2 removal is another option that can be performed in less severe cases to facilitate a less invasive and traumatic mechanical ventilation [24]. Although acute kidney injury in these patients is not common, continuous renal replacement therapies may offer in conditions of mild to severe kidney dysfunction a significant support for solute and fluid control. The same is true for left ventricular assist devices in case of refractory heart failure or albumin dialysis and HP in case of liver dysfunction and hyperbilirubinemia [25]. However, according to information collected from Chinese colleagues who faced a large proportion of patients with complicated COVID-19 syndromes in their ICUs, a significant benefit seems to have been obtained with the use of direct HP with cartridges containing highly biocompatible sorbents and microporous resins [26]. Such therapies, designed to remove the excess of circulating cytokines, seem to have displayed a remarkable benefit in terms of hemodynamic support and organ function recovery [2]. The suggested scheme of application of HA380 cartridges (Jafron Biomedical Co., China) was 2-1-1, that is, 2 units utilized for 12 h in the first 24 h and 1 unit per day utilized for 24 h in the following 2 days. In Europe, we had matured some experience with the use of Cytosorb© cartridges (CytoSorbents Corporation, NJ, USA), exactly for the same purpose of controlling deadly inflammation in critically ill and cardiac surgery patients [27, 28]. This approach may be just one of many others [29] utilizing extracorporeal therapies in these severe syndromes and will require scientific validation once the emergency of the current epidemic will be over. The suggested mechanism is the nonspecific removal of the peaks of the circulating cytokines both in the pro- and in the anti-inflammatory side. This is consistent with the “peak concentration hypothesis” suggested some time ago [30]. In presence of our inability to obtain instantaneous monitoring of biological levels of cytokines, the reasonable approach is to promote a nonspecific removal assuming that those cytokines with the highest concentration will be removed in higher amount (Fig. 1) [31]. This would facilitate a return to a less severe derangement of the immune system and to an improved level of the immunological response of the host. The same concept has been expressed by the “cytokinetic model.” In this theory, the reduction of circulating levels of cytokines may allow the immune system of the patient to redirect the immunocompetent cells to the source or site of inflammation [32]. We warn users of these techniques that together with the removal of cytokines, some drugs and antibiotics like vancomycin are also removed. In vitro models proved that [33]. In this case, a specific adjustment of antibiotic dosage in patients with bacterial infections should be carefully planned. Another adjunctive potential extracorporeal therapy is lectin affinity plasmapheresis for coronavirus trapping. Blood runs into a plasma filter, and the filtered plasma containing viral copies passes through a matrix of lectins. There is a high affinity between the viral envelope and lectins. Likewise, some viral copies are captured and the viremia is reduced [34]. This therapy should be further explored and validated. The main message the present editorial tries to convey is that the ICU staff and treating physicians should be familiar with the concept that extracorporeal therapies represent today an important strategy in critically ill patients with multiple organ dysfunction. Training and research should be planned to further develop skills and knowledge in this area where new membrane separation processes and adsorption techniques appear to be a new frontier in fighting the so-called “cytokine storm syndrome.” We will need to increase awareness of the basic principles, to study mechanisms, to optimize prescription and delivery of different techniques. We need to stimulate research and data collection to create sufficient scientific evidence. We need to prepare for the uncertain future where the frequency of these crises will be probably increasing [4]. We must retool ourselves with new strategies and new therapies, and among those, new ECOS therapies. As the ancients used to say: “Si vis pacem, para bellum,” if you want peace, get prepared to war. Disclosure Statement The authors have no conflicts of interest to declare. Funding Sources There are no funding sources to declare. Author Contributions All authors contributed equally to the manuscript and approved submission.

                Author and article information

                Blood Purif
                Blood Purif
                Blood Purification
                S. Karger AG (Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, )
                26 June 2020
                : 1-4
                aDepartment of Critical Care Nursing & Management, School of Nursing and Midwifery, Tehran University of Medical Sciences, Tehran, Iran
                bSchool of Nursing and Midwifery, Hamadan University of Medical Sciences, Hamadan, Iran
                cDepartment of Medicine (DIMED), University of Padova, Padova, Italy
                dDivision of Nephrology, Dialysis and Transplantation, International Renal Research Institute of Vicenza (IRRIV), San Bortolo Hospital, Vicenza, Italy
                eDepartment of Adults Health Nursing, School of Nursing and Midwifery, Qazvin University of Medical Sciences, Qazvin, Iran
                fDepartment of Critical Care Nursing, School of Nursing, Arak University of Medical Sciences, Arak, Iran
                gAnesthesiologist, Qom Kamkar Hospital, Qom University of Medical Sciences, Qom, Iran
                hDepartment of Intensive Care Unit, Imam Khomeini Hospital, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
                Author notes
                *Mohamad Golitaleb, Department of Critical Care Nursing, Arak University of Medical Sciences, Sardasht Street, Arak 3848176941 (Iran), m.golitaleb@
                Copyright © 2020 by S. Karger AG, Basel

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