key: cord-310166-gt6icwul authors: Yang, Xiang-Hong; Sun, Ren-Hua; Zhao, Ming-Yan; Chen, Er-Zhen; Liu, Jiao; Wang, Hong-Liang; Yang, Rong-Li; Chen, De-Chang title: Expert recommendations on blood purification treatment protocol for patients with severe COVID-19(): Recommendation and consensus date: 2020-04-28 journal: Chronic Dis Transl Med DOI: 10.1016/j.cdtm.2020.04.002 sha: doc_id: 310166 cord_uid: gt6icwul Coronavirus disease (COVID-19) was first diagnosed in Wuhan in December 2019. The World Health Organization defined the subsequent outbreak of COVID-19 worldwide as a public health emergency of international concern. Epidemiological data indicate that at least 20% of COVID-19 patients have severe disease. In addition to impairment of the respiratory system, acute kidney injury (AKI) is a major complication. Immune damage mediated by cytokine storms and concomitant AKI is a key factor for poor prognosis. Based on previous experience of blood purification for patients with severe acute respiratory syndrome and Middle East respiratory syndrome combined with clinical front-line practice, we developed a blood purification protocol for patients with severe COVID-19. This protocol is divided into four major steps. The first step is to assess whether patients with severe COVID-19 require blood purification. The second step is to prescribe a blood purification treatment for patients with COVID-19. The third step is to monitor and adjust parameters of blood purification. The fourth step is to evaluate the timing of discontinuation of blood purification. It is expected that blood purification will play a key role in effectively reducing the mortality of patients with severe COVID-19 through the standardized implementation of the present protocol. coronavirus 2 (SARS-CoV-2) was named "COVID-19" by the World Health Organization (WHO) on February 11, 2020. Its original English name, "novel coronavirus pneumonia," was revised by the National Health Commission of China on February 22, 2020 to "COVID-19," which is consistent with the WHO naming, although its Chinese name remains unchanged. So far, more than 70,000 cases have been confirmed in China. According to reports in the literature, the proportions of patients with severe and critical COVID-19 are 13.8% and 4.7%, respectively, and the overall crude case fatality rate is approximately 2.3%. 2 At present, the prevention and treatment of COVID-19 have entered critical stage, and the effective treatment of severe and critically ill patients is the key to reducing associate mortality. The "Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Sixth Edition)" 3 and "Diagnosis and Treatment Protocol for Severe and Critical Cases of Novel Coronavirus Pneumonia (Trial)" 4 both mention that in addition to active oxygen therapy and respiratory support, circulatory monitoring and support, nutritional support treatment, occurrence of acute kidney injury (AKI), and multiple organ dysfunction syndrome (MODS) should be evaluated in a timely manner. For critically ill patients with high inflammatory response, plasma purification, absorption, perfusion, blood/plasma filtration, and other blood purification techniques should be performed if possible. Excessive inflammatory response in severe COVID-19 and target organ involvement Q2 The severity of COVID-19 depends on the patient's immune status and target organ involvement. Excessive immune response can trigger cytokine storms by multiple excessive inflammatory responses throughout the body and damage the multiple target organs involved. Clinical studies have shown that the concentrations of serum inflammatory mediators, including interleukin (IL)-2, IL-7, IL-10, granulocyte colonystimulating factor, interferon-inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1a, and tumor necrosis factor a (TNF-a), were significantly higher in the sera of patients with severe COVID-19 than in those of patients with mild disease. 5 The first recent report on the pathological anatomy of dead COVID-19 patients showed that the lungs had diffuse alveolar damage with fibromucosal exudation and hyaline membrane formation, which was consistent with acute respiratory distress syndrome (ARDS). Flow cytometry revealed that the CD4 þ and CD8 þ cell counts in peripheral blood were greatly reduced; however, the double high positive ratios of human leukocyte antigen-DR (CD4 3.47%) and CD38 (CD8 39.4%) confirmed the simultaneous existence of lymphocyte hyperactivation. 6 In addition, the number of highly proinflammatory CCR4 þ CCR6 þ Th17 cells increased, and CD8 þ T cells demonstrated high cytotoxicity owing to their excessive activation, proving that cytokine stormmediated immune injury is a key factor that leads to disease aggravation and a poor prognosis. The lung is the main target organ of SARS-CoV-2. It has been reported that the incidence rate of ARDS among patients with COVID-19 ranges from 17% to 29%, 7e9 thus requiring different degrees of respiratory support. Studies have shown that the S protein of SARS-CoV-2 may bind to the angiotensin-converting enzyme 2 (ACE2) receptor, thereby damaging target organs. ACE2 is highly expressed in the kidney, nearly 100 times higher than that in the respiratory tract, theoretically suggesting that the kidney is also a major target organ of COVID-19. 10 Data from a clinical study of 59 patients with COVID-19 (including 28 severe cases) showed that 63% of patients had proteinuria (mild, 47%; moderate, 10%; severe, 6%); 27% of patients with COVID-19 had elevated urea nitrogen levels and 19% of patients with COVID-19 had elevated serum creatinine levels. 11 Three recently published clinical studies showed that the incidence rate of AKI among patients with COVID-19 was 3e7% and that 1.5%e9.0% of patients required continuous renal replacement therapy (CRRT). Among those patients, the incidence rates of AKI among patients with severe disease and critically ill patients admitted to the intensive care unit were significantly increased, ranging from 8.3% to 23.0%, and the proportion of patients who required CRRT was 5.6%e 23.0%. The rate of CRRT among patients with AKI was as high as 66.7e100%. 7e9 This medical evidence indicates that AKI is not uncommon among patients with COVID-19, particularly among those with severe disease. Therefore, for the treatment of patients with COVID-19, there should be prompt screening for AKI risk factors; routine and dynamic monitoring of urine, urine sensitive kidney function, and serum creatinine; daily assessment of AKI complications; and optimization of volume and hemodynamics. The use of nephrotoxic drugs should be avoided whenever possible, and early blood purification interventions should be performed to reduce the occurrence and progression of AKI. Basic principles of blood purification treatment for patients with severe COVID-19 Blood purification techniques include CRRT, blood/ plasma perfusion, absorption, plasma replacement, and other modes of comprehensive blood purification. The basic principles of blood purification treatment for patients with severe COVID-19 mainly include the following: (1) removal of metabolic products such as creatinine and urea nitrogen; removal of various inflammatory mediators by convection, absorption, or plasma replacement; and reshaping of the immune homeostasis; (2) regulation of volume and correction of fluid overload to help maintain hemodynamic stability in critically ill patients; (3) correction of electrolyte and acid-base balance disorders to maintain internal environment stability; (4) control of high fever; and (5) combined treatment with extracorporeal membrane oxygenation (ECMO) for extracorporeal multiple organ support. Based on the above principles, the internationally renowned critical care experts Claudio Ronco and Jean Louis Vincent jointly published an expert review titled "Coronavirus epidemic: preparing for extracorporeal organ support in intensive care" in the focus column of The Lancet Respiratory Medicine, 12 emphasizing their position on blood purification treatment for severe COVID-19: CRRT is the most commonly used blood purification method in clinical practice, and for patients with severe COVID-19 with sepsis and ARDS, blood perfusion/plasma absorption treatment can also be selected to eliminate more inflammatory medium. Based on the experiences of performing blood purification for patients with severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome combined with the first-line clinical practice of blood purification in the treatment of patients with severe COVID-19, we formulated a process of blood purification treatment for patients with severe COVID-19. The process is divided into four major steps. The first step is to assess whether patients with severe COVID-19 require blood purification. The second step is to prescribe a blood purification treatment modality for patients with severe COVID-19. The third step is to monitor the management and adjust parameters during the blood purification treatment for patients with severe COVID-19. The fourth step involves the downtime evaluation of blood purification. Details of these processes are provided in Fig. 1 . Step 1: Evaluate whether patients with severe COVID-19 require blood purification This step mainly involves the assessment of the presence or absence of indications, contraindications, and timing of implementation. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 mediator levels of patients with severe COVID-19 reach more than five times the upper limit of normal or increase >1 time within 24 hours. 14 In clinical practice, physicians in charge should comprehensively evaluate the systemic inflammatory response, severity and progress of the disease, severity of comorbid AKI, and progress of AKI among patients with COVID-19, and they should consider local medical resources and qualifications of blood purification operators to make reasonable choices. Step 2: Prescribe blood purification treatment for patients with severe COVID-19 The prescription of blood purification treatment for patients with severe COVID-19 must be formulated according to the needs of patients and physiological goals. The specific contents include the choice of mode of blood purification treatment, establishment of vascular access, choice of blood purification filter, anticoagulation scheme, treatment dose, and initial parameter settings. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 inflammatory mediators, it is recommended that filters with absorption properties (such as the AN69ST membrane or oXiris membrane) be selected. High molecular weight cutoff filters (membrane pore size up to 8e10 nm, which is approximately 2e3 times the pore size of ordinary high-throughput membranes) can also be used. However, such filters can increase the removal of albumin and other large molecules that should be monitored and supplemented in time. (2) , it is recommended that the local citric acid anticoagulation scheme be followed. A 4% trisodium citrate solution should be continuously administered at a dose of 1.2e1.5 times of the blood flow rate (ml/min) before the filter is applied. The citrate concentration should reach 3e5 mmol/L before the filter is applied, the free calcium concentration after the filter is applied should be maintained at 0.25e0.35 mmol/L, and the venous free calcium concentration should be maintained at 1.00e1.35 mmol/L. The dose of citric acid should be adjusted according to the ionized calcium concentration after the filter, and the dose of calcium chloride or calcium gluconate solution should be adjusted according to the serum concentration of ionized calcium. For patients with contraindications to citric acid but no contraindications to argatroban, argatroban can be used as an anticoagulant: continuous infusion at 1e2 mg$kg À1 $min À1 before the filter or an exact first dose (250 mg/kg) should be administered to control APTT or INR of the blood sample obtained from the peripheral vein or the arterial end of the CRRT line at less than 1.5 times of the base value, and the APTT or INR of the blood sample obtained at the venous end of the CRRT line should be maintained at 1.5e2.5 times of the base value. For patients with contraindications to the use of argatroban, heparin can be used for local anticoagulation: pre-fill the filter with 2 L of normal saline þ2500 U of plain heparin. The initial dose of plain heparin is 30 U/kg followed by 1000e1500 U/h through the arterial input. Protamine should be administered via the venous end at the initial ratio of 1 mg protamine: 100 U heparin, to adjust the ratio of heparin to protamine according to the APTT in 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 the body and the circulation circuit and to keep the APTT in the body within the normal range and the APTT in the circulation circuit at 2.0 times of the normal value. (3) Anticoagulation combined with ECMO: ECMO mainly uses systemic heparinization as the main anticoagulation method; thus, it is not necessary to administer anticoagulants during CRRT. 5. Treatment dose and parameter setting. (1) CRRT: The KDIGO AKI guidelines 16 recommend that when patients with COVID-19 are treated with CRRT, the therapeutic dose is 20e25 ml$kg À1 $h À1 when using post-dilution and 25e30 ml$kg À1 $h À1 when using predilution. When using HVHF to remove inflammatory mediators, the recommended dose is >35 ml$kg À1 $h À1 . When SCUF is used, the ultrafiltration rate is generally set to 2e5 ml/ min, which can be adjusted in time according to the patient's volume status and hemodynamic stability. In principle, the total amount of SCUF ultrafiltrate should not exceed 4 L. where the unit of body weight is kg. The duration of treatment is 2e4 hours. At the beginning of treatment, the blood flow rate in general increases gradually from 50 to 80 ml/ min to 100e150 ml/min. The separated plasma flows through the absorption column at a flow rate of 25e50 ml/min and is returned to the body. Step 3: Patient monitoring and parameter adjustment of blood purification treatment for severe COVID-19 During blood purification treatment for patients with severe COVID-19, patient monitoring should be strengthened, and the treatment parameters should be adjusted according to the monitoring content by titration. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 4. Electrolyte and acid-base balance monitoring: The blood levels of potassium, sodium, and bicarbonate should be measured every 4e6 hours during CRRT, and the blood levels of magnesium and phosphorus should be measured at least every 24 hours. The replacement fluid/ dialysate formula should be adjusted in time according to the test results. 5. Anticoagulation index monitoring: Monitor different indicators according to different anticoagulation methods (see the anticoagulation scheme for details). When there is no anticoagulation, mainly check the coagulation of the filter and help judgment based on the transmembrane pressure and filter front pressure. 6. Pulmonary imaging monitoring: Patients with severe COVID-19 show rapid changes on lung imaging. It is recommended that chest radiographs or lung computed tomography images be monitored at least every 3 days to determine the efficacy. Step 4: Downtime evaluation of blood purification for patients with severe COVID-19 There is no consensus regarding indications for downtime during blood purification treatment for patients with severe COVID-19. Downtime is recommended in the following situations. 1. Downtime of CRRT: The patient's vital signs are stable, hemodynamics are normal, ventilator conditions are significantly reduced, water electrolyte and acid-base balance disorders are corrected, and the daily urine output without diuretics is !500e1000 ml and with diuretics is !1500e2000 ml. 2. Downtime of plasma exchange and plasma perfusion/absorption: The performance of systemic inflammatory response syndrome is improved, respiratory function is improved, acute liver failure is obviously corrected, and the levels of serum inflammatory mediators such as IL-6 drop to less than twice the normal value. 14 Finally, it should be emphasized that medical personnel must protect and disinfect blood purification equipment and venues when performing blood purification treatment for patients with COVID-19. 20 None . 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 CDTM184_proof ■ 27 April 2020 ■ 9/9 A novel coronavirus from patients with pneumonia in China Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese center for disease control and prevention National Health Commission of the People's Republic of China, National Administration of Tranditional Chinese Medicine. 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