Summary
Introduction: Evidence shows that continuous renal replacement therapy (CRRT) and hemodialysis may be effective in the treatment of Coronavirus disease-2019 (COVID-19). This study aimed to compare the effects of CRRT and hemodialysis on complications, vital signs, and laboratory parameters in patients with COVID-19.
Materials and Methods: This cross-sectional study was performed on 113 patients with COVID-19 who underwent hemoperfusion in Kosar Hospital of Semnan city (Iran) between 2020 and 2021. The patients were divided into two groups, the CRRT hemoperfusion group (n=49) and the hemodialysis group (n=64). A checklist was used for collecting data, which included demographic variables, history of underlying diseases, vital signs, laboratory parameters, complications, and various outcomes, which were extracted through interviews with patients or companions and in medical records. IBM Statistical Package for the Social Sciences Statistics for Windows version 26 was used for data analysis.
Results: The time from hemoperfusion to hospital discharge (3.84±4.51 vs. 5.92±4.16 day), duration of intubation (0.33±0.94 vs. 1.84±3.42), death after hemoperfusion (64.06 vs. 26.5%), situational instability (21.9 vs. 8.2%), and death during hemoperfusion (14.1 vs. 0%) were significantly lower in the CRRT group than in the hemodialysis group (p<0.05). In the repeated-measures analysis of variance (ANOVA) test, the two groups demonstrated a statistically significant difference in lactate dehydrogenase, alkaline phosphatase, white blood cell count, and C-reactive protein at different time points; thus, the mean of these variables was significantly lower after hemoperfusion in the CRRT group than in the hemodialysis group (p<0.05).
Conclusion: Continuous renal replacement therapy hemoperfusion can be effective in the recovery process of patients with COVID-19 because the length of hospital stay, intubation period, situational instability, and mortality during and after hemoperfusion are less than those of hemodialysis.
Introduction
Coronavirus disease-2019 (COVID-19) is a pneumonic pandemic caused by Severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2). This disease was first detected in December 2019 in Wuhan City, China[1-3].
In mild COVID-19, the immune response can eliminate the SARS-CoV-2, possibly with specific antiviral responses of a type 1 interferon and responses of Th1 CD4+ cells and CD8+ T cells. In severe cases, there may be an initial delay in antiviral responses, followed by an increase in the production of inflammatory cytokines and the movement of monocytes and neutrophils into the lungs, leading to a cytokine storm. These cytokines, including interleukins 1, 6, and 12 (IL-1, IL-6, and IL-12, respectively) and tumor necrosis factor-alpha, lead to increased vascular permeability and eventually respiratory failure. High levels of cytokines also indicate a poor prognosis of SARS-CoV-2. Various studies have suggested that “cytokine storms” may increase the risk of death from COVID-19. Laboratory findings include lymphocyte deficiency, increased inflammatory markers such as C-reactive protein (CRP) and increased D-dimer as activation of cascade coagulation[4-7]. In addition, hemoperfusion was found to be an effective procedure for killing cytokines and reducing their inflammatory effects on other diseases. Hemoperfusion, as a blood purification procedure, has many benefits compared with other nonselective forms of in vitro detoxification[8-10].
In respiratory infections, an increase in proinflammatory cytokines of the blood creates a cytokine storm that can cause severe sepsis, septic shock, and ultimately increase mortality. Some studies have reported that the use of hemoperfusion and clearance of cytokines and inflammatory mediators from the blood may improve the normal course of the disease by improving the patient’s respiratory symptoms and peripheral oxygen saturation (SpO2)[11-13]. However, to our knowledge, no comparative study has examined the effect of continuous renal replacement therapy (CRRT) and hemodialysis on COVID-19; therefore, this study aimed to compare the effect of CRRT hemoperfusion and hemodialysis on complications, vital signs, and laboratory parameters in patients with COVID-19.
Methods
Study Design and Subjects
This cross-sectional study enrolled patients with COVID-19 who were hospitalized in Kosar Hospital of Semnan (Iran) between 2020 and 2021. The study was conducted as a census; thus, all patients with COVID-19 who underwent hemoperfusion in this hospital from February 2020 to May 2021 were examined. Then, the patients were divided into two groups: the CRRT hemoperfusion group (n=49) and the hemodialysis group (n=64). The inclusion criteria were as follows: age 25-90 years, COVID-19 confirmed by a positive reverse-transcription polymerase chain reaction, lung involvement on computed tomography, and consent to undergo hemoperfusion. The exclusion criteria were as follows: incomplete medical record, pregnancy, and reluctance to participate in the study.
Treatment
Hemoperfusion: Hemoperfusion was performed through femoral vein catheters with a blood flow rate of 250-300 mL/min. Two types of hemoperfusion cartridges were used: Jafron© (HA330) or CytoSorb® 300 for 4 and 8-12 h, respectively.
Continuous renal replacement therapy: The CRRT dose volume was adjusted according to patient needs, although the CRRT dose was usually 20-25 mL/kg/h, and access was achieved through a central venous catheter placed in one of the large central veins. The cartridges used in CRRT were Jafron© (HA330) or CytoSorb® 300 for 8 or 12-24 h.
Data Collection
A checklist was used to collect data, including demographic variables (age, sex, BMI, and smoking), history of underlying diseases [diabetes, hypertension, hyperlipidemia, cardiovascular diseases, kidney transplant, chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), asthma, and cancer], vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, body temperature, and SpO2), clinical signs, laboratory parameters [lactate dehydrogenase (LDH), alkaline phosphatase (ALP), white blood count (WBC), CRP, fasting blood sugar (FBS), blood urea nitrogen (BUN), creatinine (Cr), erythrocyte sedimentation rate (ESR), ferritin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), partial thromboplastin time (PTT), prothrombin time (PT), international normalized ratio (INR), hemoglobin (HB), hematocrit (HCT), and platelet count (PLT)], complications, and various outcomes (duration of hospitalization, duration of intubation, death during and after hemoperfusion, hemoperfusion frequency, extubation frequency, fever and chills, gastrointestinal bleeding, coagulation disorders, and situational instability) that were partly extracted through interviews with patients or companions and partly extracted from medical records.
Ethical Considerations
Before data collection, the aims of the study were explained to the patients or their caregivers, and informed consent was obtained from them. In addition, this study was performed according to the principles expressed in the Declaration of Helsinki and was approved by the Deputy of the Research and Ethics Committee of Semnan University of Medical Sciences (Iran) (IR.SEMUMS.REC.1400.172, date: 26.10.2021).
Statistical Analysis
Data were analyzed using IBM Statistical Package for the Social Sciences Statistics for Windows version 26 (IBM Corp., Armonk, NY, USA). For descriptive analyses, the mean and standard deviation or number (%) was used. Then, independent samples t-test (quantitative variables) and chi-squared test (qualitative variables) were used to compare baseline data and complications in the two groups. Finally, repeated-measures analysis of variance (ANOVA) test was used to compare vital signs and laboratory parameters at different time points (two times before and after hemoperfusion) in the two groups, and p value <0.05 was considered a significant level.
Results
A total of 113 patients with COVID-19 underwent hemoperfusion. The mean ages of the patients in the CRRT and hemodialysis groups were 52.67±13.65 and 54.86±14.20 years, respectively. There were 30 (61.2%) and 40 (62.5) male patients, respectively. The mean body mass index (BMI) values were 27.77±4.17 and 27.96±3.97 kg/m2, respectively. The mean rates of pulmonary involvement (%) in the two groups were 58.57±16.20% and 63.44±16.6%, respectively. No significant difference was found between the two groups in terms of age, sex, BMI, history of smoking, and underlying diseases, such as hyperlipidemia, cardiovascular diseases, CKD, COPD, asthma, and cancer (p>0.05). However, a statistically significant difference was found in the history of diabetes and hypertension; thus, the percentage of patients with diabetes (64.1 vs. 18.4%) and hypertension (53.1 vs. 26.5%) in the hemodialysis group was higher than that in the CRRT group (p<0.05) (Table 1).
Table 2 compares the duration of hospitalization, complications, and consequences of hemoperfusion in the two groups. The time from hemoperfusion to hospital discharge (3.84±4.51 vs. 5.92±4.16 day), time from hospitalization to intubation (2.24±4.85 vs. 4.81±5.50 day), and duration of intubation (0.33±0.94 vs. 1.84±3.42 day) were significantly lower in CRRT group than in the hemodialysis group (p<0.05). In addition, the rates (%) of death after hemoperfusion (64.06 vs. 26.5%), situational instability (21.9 vs. 8.2%), and death during hemoperfusion (14.1 vs. 0%) were significantly lower in the CRRT group than in the hemodialysis group (p<0.05). However, in terms of the length of hospitalization, time from hospitalization to the start of hemoperfusion, hemoperfusion frequency, extubation frequency, death 24 h after hemoperfusion, and complications (fever and chills, gastrointestinal bleeding, and coagulation disorders), no significant difference was observed between the two groups (p>0.05).
In the present study, the results of repeated-measures ANOVA test showed no statistically significant difference between the two groups in terms of systolic and diastolic blood pressure, heart rate, respiratory rate, body temperature, and SpO2 at different time points (p>0.05) (Table 3).
Table 4 shows the comparison of the mean of laboratory parameters in the hemodialysis and CRRT groups at different time points before and after hemoperfusion by repeated-measures ANOVA test. A statistically significant difference in LDH, ALP, WBC, and CRP at different time points (p<0.05) was found between the groups; thus, the mean of these variables after hemoperfusion was significantly lower in the CRRT group than in the hemodialysis group. However, no statistically significant difference in FBS, BUN, Cr, ESR, ferritin, AST, ALT, PTT, PT, INR, HB, HCT, and PLT at different time points was found between the groups (p>0.05) (Table 4).
Discussion
Hemoperfusion is an extracorporeal blood purification procedure that involves the passage of whole anticoagulant blood through a device that contains absorbent particles. Similar to other extracorporeal methods, such as hemodialysis and hemofiltration, the patient’s blood is filtered while passing through the device and then returns to the patient via an intravenous access. In some centers, this method was used to eliminate toxins in poisoning and remove cytokines in patients with sepsis[14]. The use of hemoperfusion to remove inflammatory cytokines produced by COVID-19 from the bloodstream and prevent the progression of the inflammatory process in the lungs and other organs may be effective.
The results of our study were in line with the findings of some related studies. For example, Asgharpour et al.[15] evaluated the effect of hemoperfusion on patients with severe COVID-19 and found that 6 of 11 patients recovered after hemoperfusion. The mean SpO2 increased significantly after three sessions of the intervention (89.60±3.94% to 92.13±3.28% after the intervention). Serum levels of CRP (136.25±84.39 to 78.25±38.67 mg/L, p=0.016) and IL-6 (139.70±105.62 to 72.06±65.87 pg/mL, p=0.073) also decreased. Finally, the authors concluded that hemoperfusion may be effective in improving patients with COVID-19. In addition, Dastan et al.[16] evaluated the effectiveness of CRRT using a disposable hemoperfusion cartridge in a 54-year-old man with COVID-19; after 4 days of hospitalization, the patient’s clinical condition worsened, and he underwent intubation for invasive mechanical ventilation. SpO2 decreased to 82%. Therefore, the patient underwent hemoperfusion by CRRT because of cytokine storm and hypoxemia. After three CRRT sessions, the SpO2 increased to 95%, and no specific laboratory abnormalities were observed during CRRT. Finally, the researchers suggested that CRRT with a disposable hemoperfusion cartridge may be a promising option for reducing inflammatory cytokines in patients with COVID-19. In Iran, Haleh Mikaeili et al.[17] and Alavi Darazam et al.[18] have also shown that hemoperfusion may be effective in reducing the mortality of patients with severe COVID-19.
In a case report study, a 73-year-old man developed myocardial infarction about a month before the onset of COVID-19 symptoms. Owing to episodic conditions and worsening symptoms, cytokine storm was considered the main cause of postural instability, and the patient became a candidate for hemoperfusion. During hemoperfusion, the symptoms improved, and the Sequential Organ Failure Assessment scores that peaked during hospitalization following hemoperfusion decreased significantly. Finally, the study indicated that cytokine storm could be a good indicator for predicting COVID-19 severity and mortality and that hemoperfusion may be an appropriate treatment to reduce COVID-19 complications[8].
Generally, various mechanisms have been proposed for severe COVID-19 and related complications. Cytokine storm is one of the mechanisms of interest. IL-6 is the most important cause of cytokine storm. When a cytokine storm occurs, the immune response intensifies, and subsequently, COVID-19 progresses rapidly[19-22]. One of the treatment strategies to reduce and stop the production of inflammatory cytokines is hemoperfusion, which can be effective in patients with severe COVID-19. Studies have shown that improving SpO2 during blood purification is more associated with a cytokine reduction than volume load reduction because in the CRRT method, the same amount of fluid is removed from the patient and the same amount of fluid is replaced. In addition, reducing cytokines prevent damage to various organs, especially in patients who are in the early stages of cytokine storms[23-25].
Study Limitations
C-reactive protein is another biomarker that is elevated in the early stages of COVID-19, and a higher level is associated with severe lung damage. A study showed that this marker also decreases after hemoperfusion[26]. These studies have several strengths and weaknesses. The most important weakness of the present study is the lack of random allocation of patients to intervention groups; thus, the two groups were incomparable in terms of many known and unknown confounding variables. Therefore, clinical trial studies with random allocation are necessary. One of the study’s strengths is the nearly appropriate sample size in the two groups, and the comparative nature of the study because most of the studies conducted in this field were case reports or case series and did not have a control group.
Conclusion
This study suggests that CRRT hemoperfusion can be effective in the recovery process of patients with COVID-19 because the length of hospital stay, intubation period, situational instability, and mortality during and after hemoperfusion are less than those of hemodialysis. However, multicenter clinical trial studies with appropriate sample sizes are recommended.
Acknowledgments
This article is extracted from Zahra Shaabani Khatib’s thesis of general medicine in Semnan University of Medical Sciences, Iran. We would like to express our sincere gratitude to the staff of Kosar Hospital of Semnan city (Iran) for their cooperation in this research.
Ethics
Ethics Committee Approval: This study was performed according to the principles expressed in the Declaration of Helsinki and was approved by the Deputy of the Research and Ethics Committee of Semnan University of Medical Sciences (Iran) (IR.SEMUMS.REC.1400.172, date: 26.10.2021).
Informed Consent: Consent form was filled out by all participants.
Peer-review: Externally and internally peer-reviewed.
Authorship Contributions
Surgical and Medical Practices: S.I., M.M., S.L., Concept: M.M., Z.S.K., Design: S.I., M.M., K.M., Data Collection or Processing: Z.S.K., S.L., K.M., Analysis or Interpretation: S.L., K.M., Literature Search: S.I., M.M., Z.S.K., S.L., Writing: S.I., M.M., Z.S.K., S.L., K.M.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The study was supported by Deputy of Research of Semnan University of Medical Sciences, Semnan, Iran.
