The effects of 0.9% saline versus Plasma-Lyte 148 on renal function as assessed by creatinine concentration in patients undergoing major surgery: A single-centre double-blinded cluster crossover trial

Objectives Saline and Plasma-Lyte have different physiochemical contents; consequently, they may differently affect patients’ renal function. We compared the effects of fluid therapy with 0.9% saline and with Plasma-Lyte 148 on renal function as assessed by creatinine concentration among patients undergoing major surgery. Methods We conducted a prospective, double-blinded cluster crossover trial comparing the effects of the two fluids on major surgery patients. The primary aim was to establish the pilot feasibility, safety and preliminary efficacy evidence base for a large interventional trial to establish whether saline or Plasma-Lyte is the preferred crystalloid fluid for managing major surgery patients. The primary efficacy outcome was the proportion of patients with changes in renal function as assessed by creatinine concentration during their index hospital admission. We used changes in creatinine to define acute kidney injury (AKI) according to the RIFLE criteria. Results The study was feasible with 100% patient and clinician acceptance. There were no deviations from the trial protocol. After screening, we allocated 602 patients to saline and 458 to Plasma-Lyte. The median (IQR) volume of intraoperative fluid received was 2000 mL (1000:2000) in both groups. Forty-nine saline patients (8.1%) and 49 Plasma-Lyte patients (10.7%) developed a postoperative AKI (adjusted incidence rate ratio [aIRR]: 1.34; 95% CI: 0.93–1.95; p = 0.120). No differences were observed in the development of postoperative complications (aIRR: 0.98; 95% CI: 0.89–1.08) or the severity of the worst complication (aIRR: 1.00; 95% CI: 0.78–1.30). The median (IQR) length of hospital stay was six days (3:11) for the saline group and five days (3:10) for the Plasma-Lyte group (aIRR: 0.85; 95% CI: 0.73–0.98). There were no serious adverse events relating to the trial fluids, nor were there fluid crossover or contamination events. Conclusions The study design was feasible to support a future follow-up larger clinical trial. Patients treated with saline did not demonstrate an increased incidence of postoperative AKI (defined as changes in creatinine) compared to those treated with Plasma-Lyte. Our findings imply that clinicians can reasonably use either solution intraoperatively for adult patients undergoing major surgery. Trial registration Registry: Australian New Zealand Clinical Trials Registry; ACTRN12613001042730; URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=364988.

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Impact of Cardiac Function Improvement on Cardiac Surgery Associated Acute Kidney Injury for Patients with Preoperative Renal Dysfunction

10.21203/rs.3.rs-58733/v1 ◽

2020 ◽

Author(s):

Jiarui Xu ◽

Xin Chen ◽

Jing Lin ◽

Yang Li ◽

Bo Shen ◽

...

Keyword(s):

Acute Kidney Injury ◽

Renal Function ◽

Cardiac Surgery ◽

Cardiac Function ◽

Renal Dysfunction ◽

Significant Risk ◽

Kidney Injury ◽

Normal Function ◽

Function Group ◽

Postoperative Aki

Abstract Background: We aim to investigate whether the postoperative cardiac function improve or not would affect the risk of cardiac surgery associated acute kidney injury (AKI) for patients with preoperative renal dysfunction. Method: Data from patients underwent cardiac surgery from April 2012 to February 2016 were collected. Renal dysfunction was defined as preoperative SCr >1.2 mg/dL (females) or >1.5 mg/dL (males). Patients were grouped as normal renal function group, renal dysfunction with chronic kidney disease (CKD group), and non CKD group. △LVEF=postoperative LVEF - preoperative LVEF. Cardiac function improved was defined as △LVEF ≥10. Patients were further divided into non CKD & cardiac function improved (non CKD+), non CKD & cardiac function not improved (non CKD-), CKD & cardiac function improved (CKD+) and CKD & cardiac function not improved (CKD-) subgroups.Results: A total of 8,661 patients were allocated as normal renal function (n=7,903), non CKD(n = 662) and CKD (n = 136) groups. Both non CKD and CKD groups had higher AKI incidence than normal function group (39.5% vs 30.0%, P < 0.001; 61.8% vs 30.0%, P<0.001), and non CKD+ group had the similar AKI incidence with normal function group (30.9% vs 30.0%, P=0.729). Multivariate logistic regression analysis revealed that non CKD-, CKD+ and CKD- were significant risk factors, whereas non CKD+ was not a significant risk factor for postoperative AKI. The SCr at discharge in non CKD+ subgroup was significantly lower than its preoperative SCr (1.4 ± 0.8 vs 1.7 ± 0.9 mg/dL, P = 0.020).Conclusions: For renal dysfunction patients with no CKD, the risk of postoperative AKI did not exist if the cardiac function improved after surgery. For CKD patients, the risk of postoperative AKI increase regardless whether the cardiac function improved or not.

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Intravenous Fluid of Choice in Major Abdominal Surgery: A Systematic Review

Critical Care Research and Practice ◽

10.1155/2020/2170828 ◽

2020 ◽

Vol 2020 ◽

pp. 1-19

Author(s):

Seechad Noonpradej ◽

Osaree Akaraborworn

Keyword(s):

Systematic Review ◽

Renal Function ◽

Abdominal Surgery ◽

Kidney Injury ◽

Length Of Hospital Stay ◽

Volume Effect ◽

Intravenous Fluid ◽

Major Abdominal Surgery ◽

Intravascular Volume ◽

Hemodynamic Status

Background. Intravenous fluid therapy plays a role in maintaining the hemodynamic status for tissue perfusion and electrolyte hemostasis during surgery. Recent trials in critically ill patients reported serious side effects of some types of fluids. Since the most suitable type of fluid is debatable, a consensus in perioperative patients has not been reached. Method. We performed a systematic review of randomized control trials (RCTs) that compared two or more types of fluids in major abdominal surgery. The outcomes were related to bleeding, hemodynamic status, length of hospital stay, and complications, such as kidney injury, electrolyte abnormality, major cardiac adverse event, nausea, vomiting, and mortality. A literature search was performed using Medline and EMBASE up to December 2019. The data were pooled to investigate the effect of fluid on macrocirculation and intravascular volume effect. Results. Forty-three RCTs were included. Eighteen fluids were compared: nine were crystalloids and nine were colloids. The results were categorized into macrocirculation and intravascular volume effect, microcirculation, anti-inflammatory parameters, vascular permeability, renal function (colloids), renal function and electrolytes (crystalloids), coagulation and bleeding, return of bowel function, and postoperative nausea vomiting (PONV). We found that no specific type of fluid led to mortality and every type of colloid was equivalent in volume expansion and did not cause kidney injury. However, hydroxyethyl starch and dextran may lead to increased bleeding. Normal saline can cause kidney injury which can lead to renal replacement therapy, and dextrose fluid can decrease PONV. Conclusion. In our opinion, it is safe to give a balanced crystalloid as the maintenance fluid and give a colloid, such as HES130/0.4, 4% gelatin, or human albumin, as a volume expander.

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Acetate Ringer's solution versus 0.9% saline for septic patients: study protocol for a randomized controlled multicenter crossover trial

10.21203/rs.3.rs-21846/v1 ◽

2020 ◽

Author(s):

Fang Liu ◽

Jing Zhang ◽

Yuan Zhu ◽

Lianjiu Su ◽

Yiming Li ◽

...

Keyword(s):

Septic Shock ◽

Acute Kidney Injury ◽

Renal Function ◽

Renal Replacement Therapy ◽

Replacement Therapy ◽

Intravenous Infusion ◽

Crossover Trial ◽

Kidney Injury ◽

Hospital Death ◽

Ringer’S Solution

Abstract Background: The previous study demonstrated that there were no significant differences between saline and balanced crystalloid solution infused in critical illness. However, the sepsis subgroup analysis showed the statistical difference. Thus, we will specifically focus on septic patients in this study to compare the effects of saline and balanced solution. We hypothesize that effects of saline on acute kidney injury (AKI) are related to the underline AKI severity and total volumes of infusion. Methods/design: The investigators designed a pragmatic, multi-centered crossover trial recruiting 312 patients who are diagnosed as sepsis/septic shock in the intensive care unit (ICU) and will be assigned with either acetate Ringer's solution or saline in the corresponding month. Patients with an end-stage renal disease (ESRD) or who need renal replacement therapy (RRT) prior to or at the time of enrollment are excluded. Enrolled patients will be regarded as with mild, moderate or severe sepsis on the basis of the severity of their illness, and will be divided into subgroups according to their initial renal function and various intravenous infusion volumes when being analyzed. The primary outcome is major adverse kidney events (MAKE), including the composite of in-hospital death, receipt of new renal replacement therapy, or persistent renal dysfunction. Secondary outcomes include 28 days-mortality, internal environment disturbance, incidence and duration of vasoactive drug treatment, duration of mechanical ventilation, duration of RRT and ICU and hospital length of stay. Results and Conclusions: To our knowledge, this study will be the first to focus on septic patients and provide credible and evident data on the comparison of outcome between acetate Ringer’s solution and saline for intravenous infusion in adult septic patients on the basis of baseline renal function and infusion volumes taken into consideration. Trial registration: ClinicalTrials.gov, identifiers: NCT03685214. Registered on August 15, 2018. https://clinicaltrials.gov/ct2/show/NCT03685214 Keywords: sepsis; septic shock; acute kidney injury; saline; acetate Ringer's solution.

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Antithrombin nanoparticles improve kidney reperfusion and protect kidney function after ischemia-reperfusion injury

AJP Renal Physiology ◽

10.1152/ajprenal.00457.2014 ◽

2015 ◽

Vol 308 (7) ◽

pp. F765-F773 ◽

Cited By ~ 18

Author(s):

Junjie Chen ◽

Chandu Vemuri ◽

Rohun U. Palekar ◽

Joseph P. Gaut ◽

Matthew Goette ◽

...

Keyword(s):

Renal Function ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Vascular Endothelial Cell ◽

Kidney Injury ◽

Warm Ischemia ◽

Thrombin Inhibitor ◽

Direct Role ◽

Creatinine Concentration

In the extension phase of acute kidney injury, microvascular thrombosis, inflammation, vasoconstriction, and vascular endothelial cell dysfunction promote progressive damage to renal parenchyma after reperfusion. In this study, we hypothesized that direct targeting and pharmaceutical knockdown of activated thrombin at the sites of injury with a selective nanoparticle (NP)-based thrombin inhibitor, PPACK (phenylalanine-proline-arginine-chloromethylketone), would improve kidney reperfusion and protect renal function after transient warm ischemia in rodent models. Saline- or plain NP-treated animals were employed as controls. In vivo 19F magnetic resonance imaging revealed that kidney nonreperfusion was evident within 3 h after global kidney reperfusion at 34 ± 13% area in the saline group and 43 ± 12% area in the plain NP group and substantially reduced to 17 ± 4% (∼50% decrease, P < 0.05) in the PPACK NP pretreatment group. PPACK NP pretreatment prevented an increase in serum creatinine concentration within 24 h after ischemia-reperfusion, reflecting preserved renal function. Histologic analysis illustrated substantially reduced intrarenal thrombin accumulation within 24 h after reperfusion for PPACK NP-treated kidneys (0.11% ± 0.06%) compared with saline-treated kidneys (0.58 ± 0.37%). These results suggest a direct role for thrombin in the pathophysiology of AKI and a nanomedicine-based preventative strategy for improving kidney reperfusion after transient warm ischemia.

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Does Goal-directed Fluid Therapy Affect Postoperative Orthostatic Intolerance?

Anesthesiology ◽

10.1097/aln.0b013e31829ce4ea ◽

2013 ◽

Vol 119 (4) ◽

pp. 813-823 ◽

Cited By ~ 30

Author(s):

Morten Bundgaard-Nielsen ◽

Øivind Jans ◽

Rasmus G. Müller ◽

André Korshin ◽

Birgitte Ruhnau ◽

...

Keyword(s):

Stroke Volume ◽

Fluid Therapy ◽

Orthostatic Intolerance ◽

Length Of Hospital Stay ◽

Early Mobilization ◽

Postoperative Recovery ◽

Major Surgery ◽

Control Group ◽

Open Radical Prostatectomy ◽

Double Blinded

Abstract Background: Early mobilization is important for postoperative recovery but is limited by orthostatic intolerance (OI) with a prevalence of 50% 6 h after major surgery. The pathophysiology of postoperative OI is assumed to include hypovolemia besides dysregulation of vasomotor tone. Stroke volume–guided fluid therapy, so-called goal-directed therapy (GDT), corrects functional hypovolemia, and the authors hypothesized that GDT reduces the prevalence of OI after major surgery and assessed this in a prospective, double-blinded trial. Methods: Forty-two patients scheduled for open radical prostatectomy were randomized into standard fluid therapy (control group) or GDT groups. Both groups received a fixed-volume crystalloid regimen supplemented with 1:1 replacement of blood loss with colloid, and in addition, the GDT group received colloid to obtain a maximal stroke volume (esophageal Doppler). The primary outcome was the prevalence of OI assessed with a standardized mobilization protocol before and 6 h after surgery. Hemodynamic and hormonal orthostatic responses were evaluated. Results: Twelve (57%) versus 15 (71%) patients in the control and GDT groups (P = 0.33), respectively, demonstrated OI after surgery, group difference 14% (CI, −18 to 45%). Patients in the GDT group received more colloid during surgery (1,758 vs. 1,057 ml; P = 0.001) and reached a higher stroke volume (102 vs. 89 ml; P = 0.04). OI patients had an increased length of hospital stay (3 vs. 2 days; P = 0.02) and impaired hemodynamic and norepinephrine responses on mobilization. Conclusion: GDT did not reduce the prevalence of OI, and patients with OI demonstrated impaired cardiovascular and hormonal responses to mobilization.

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CIRRHOTIC PATIENTS WITH ACUTE KIDNEY INJURY (AKI) HAVE HIGHER MORTALITY AFTER ABDOMINAL HERNIA SURGERY

ABCD Arquivos Brasileiros de Cirurgia Digestiva (São Paulo) ◽

10.1590/0102-672020210002e1622 ◽

2021 ◽

Vol 34 (3) ◽

Author(s):

Liliana DUCATTI ◽

Luciana B. P. HADDAD ◽

Alberto MEYER ◽

Lucas S. NACIF ◽

Rubens M. ARANTES ◽

...

Keyword(s):

Acute Kidney Injury ◽

Renal Function ◽

Emergency Surgery ◽

Kidney Injury ◽

Abdominal Hernia ◽

Hernia Surgery ◽

Baseline Creatinine ◽

Cirrhotic Patients ◽

Postoperative Aki

ABSTRACT Background: The incidence of abdominal hernia in cirrhotic patients is as higher as 20%; in cases of major ascites the incidence may increase up to 40%. One of the main and most serious complications in cirrhotic postoperative period (PO) is acute kidney injury (AKI). Aim: To analyze the renal function of cirrhotic patients undergoing to hernia surgery and evaluate the factors related to AKI. Methods: Follow-up of 174 cirrhotic patients who underwent hernia surgery. Laboratory tests including the renal function were collected in the PO.AKI was defined based on the consensus of the ascite´s club. They were divided into two groups: with (AKI PO) and without AKI . Results: All 174 patients were enrolled and AKI occurred in 58 (34.9%). In the AKI PO group, 74.1% had emergency surgery, whereas in the group without AKI PO it was only 34.6%.In the group with AKI PO, 90.4% presented complications, whereas in the group without AKI PO they occurred only in 29.9%. Variables age, baseline MELD, baseline creatinine, creatinine in immediate postoperative (POI), AKI and the presence of ascites were statistically significant for survival. Conclusions: There is association between AKI PO and emergency surgery and, also, between AKI PO and complications after surgery. The factors related to higher occurrence were initial MELD, basal Cr, Cr POI. The patients with postoperative AKI had a higher rate of complications and higher mortality.

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Angiotensin II Receptor Blockers but Not Angiotensin-Converting Enzyme Inhibitors Are Associated With a Reduced Risk of Acute Kidney Injury After Major Surgery

Frontiers in Pharmacology ◽

10.3389/fphar.2021.662301 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shao-Yu Yang ◽

Tao-Min Huang ◽

Tai-Shuan Lai ◽

Nai-Kuan Chou ◽

Chun-Hao Tsao ◽

...

Keyword(s):

Enzyme Inhibitors ◽

Kidney Injury ◽

Angiotensin Converting Enzyme Inhibitors ◽

Major Surgery ◽

Converting Enzyme Inhibitors ◽

All Cause Mortality ◽

Receptor Blockers ◽

Postoperative Aki ◽

Reduced Risk

Objective: We investigated the respective effects of preoperative angiotensin-converting-enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) on the incidence of postoperative acute kidney injury (AKI) and mortality.Methods: In this nested case-control study, we enrolled 20,276 patients who received major surgery. We collected their baseline demographic data, comorbidities and prescribed medication, the outcomes of postoperative AKI and mortality. AKI was defined by the criteria suggested by KDIGO (Kidney disease: Improving Global Outcome). Logistic regression was used to assess the impact of exposure to ACEIs or ARBs.Results: Compared with patients without ACEI/ARB, patient who received ARBs had a significantly lower risk for postoperative AKI (adjusted odds ratio (OR) 0.82, p = 0.007). However, ACEI users had a higher risk for postoperative AKI than ARB users (OR 1.30, p = 0.027), whereas the risk for postoperative AKI was not significantly different between the ACEI users and patients without ACEI/ARB (OR 1.07, p = 0.49). Compared with patients without ACEI/ARB, both ACEI and ARB users were associated with a reduced risk of long-term all-cause mortality following surgery (OR 0.47, p = 0.002 and 0.60, p < 0.001 in ACEI and ARB users, respectively), without increasing the risk of hyperkalemia during the index hospitalization (p = 0.20). The risk of long-term all-cause mortality following surgery in ACEIs and ARBs users did not differ significantly (OR 0.74, p = 0.27). Furthermore, the higher the defined daily dose of ARB, the better the protection against AKI provided.Conclusion: Our study revealed that preoperative use of ARBs was associated with reduced postoperative AKI, which is better in high quantity, whereas preoperative use of ACEIs or ARBs were both associated with reduced mortality and did not increase the risk of hyperkalemia.

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Risk Factors for Acute Kidney Injury Requiring Renal Replacement Therapy after Orthotopic Heart Transplantation in Patients with Preserved Renal Function

Journal of Clinical Medicine ◽

10.3390/jcm10184117 ◽

2021 ◽

Vol 10 (18) ◽

pp. 4117

Author(s):

René M‘Pembele ◽

Sebastian Roth ◽

Alexandra Stroda ◽

Giovanna Lurati Buse ◽

Stephan U. Sixt ◽

...

Keyword(s):

Risk Factors ◽

Acute Kidney Injury ◽

Renal Function ◽

Renal Replacement Therapy ◽

Heart Transplantation ◽

Replacement Therapy ◽

Plasma Levels ◽

Kidney Injury ◽

Orthotopic Heart Transplantation ◽

Postoperative Aki

Acute kidney injury (AKI), requiring renal replacement therapy (RRT). is a serious complication after orthotopic heart transplantation (HTX). In patients with preexisting impaired renal function, postoperative AKI is unsurprising. However, even in patients with preserved renal function, AKI requiring RRT is frequent. Therefore, this study aimed to identify risk factors associated with postoperative AKI requiring RRT after HTX in this sub-cohort. This retrospective cohort study included patients ≥18 years of age with preserved renal function (defined as preoperative glomerular filtration rate ≥60 mL/min) who underwent HTX between 2010 and 2021. In total, 107 patients were included in the analysis (mean age 52 ± 12 years, 78.5% male, 45.8% AKI requiring RRT). Based on univariate logistic regression, use of extracorporeal membrane oxygenation, postoperative infection, levosimendan therapy, duration of norepinephrine (NE) therapy and maximum daily increase in tacrolimus plasma levels were chosen to be included into multivariate analysis. Duration of NE therapy and maximum daily increase in tacrolimus plasma levels remained as independent significant risk factors (NE: OR 1.01, 95%CI: 1.00–1.02, p = 0.005; increase in tacrolimus plasma level: OR 1.18, 95%CI: 1.01–1.37, p = 0.036). In conclusion, this study identified long NE therapy and maximum daily increase in tacrolimus plasma levels as risk factors for AKI requiring RRT in HTX patients with preserved renal function.

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Impact of Ivabradine on renal function in septic patient with early renal impairment

Ain-Shams Journal of Anesthesiology ◽

10.1186/s42077-021-00162-6 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Amr Sobhy ◽

Lobna A. Saleh ◽

Aktham Adel Shoukry

Keyword(s):

Heart Rate ◽

Renal Function ◽

Renal Impairment ◽

Septic Patient ◽

Kidney Injury ◽

Length Of Hospital Stay ◽

Multiple Organ ◽

Clinical Trial Registry ◽

Versus Group ◽

Group I

Abstract Background Acute kidney injury (AKI) with sepsis increases mortality significantly. The pathophysiology of AKI during sepsis is complex and multifactorial. Lower heart rate is associated with better survival in patients with multiple organ dysfunction syndrome (MODS), a disease mostly caused by sepsis. In our study, we hypnotized that use of ivardrabine as heart rate reducing agent in septic patient with renal impairment may improve renal function. Results Fifty patients with sepsis with early renal impairment were divided in 1: 1 ratio to receive Ivabradine (group I) or not (group C). The average age of the included patients was almost 45 years, chest disorders were the main cause of sepsis in both groups. There were statistically significant differences between both groups in terms of reduction of heart rate group (I) (68.13 ± 3.34) versus (group C) (87.04 ± 3.23) and (P < 0.001) also, improvement in eGFR by Cystatin c in group (I) (103.32 ± 6.96) versus (group C) (96.25 ± 6.36) and (P < 0.001) also vasopressor dosage consumption (P < 0.001). As regards secondary outcomes, there were no statistically significant differences between study’s groups in terms of length of hospital stay (P = 0.390), need for hemodialysis (P = 0.384), and mortality (P = 1.000). Conclusions We concluded that Ivabradine as an adjuvant therapy in septic patients with renal impairment is promising agent to reduce such impairment. Trial registration Pan African Clinical Trial Registry: Identification number for the registry is PACTR201911806644230.

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The Use of Standardized Brazilian Green Propolis Extract (EPP-AF) as an Adjunct Treatment for Hospitalized COVID-19 Patients (BeeCovid2): A Structured Summary of a Study Protocol for a Randomized Controlled Trial

10.21203/rs.3.rs-617827/v1 ◽

2021 ◽

Author(s):

Marcelo Augusto Duarte Silveira ◽

Sergio Pinto de Souza ◽

Erica Batista dos Santos Galvão ◽

Maurício Brito Teixeira ◽

Marcel Miranda Dantas Gomes ◽

...

Keyword(s):

Controlled Trial ◽

Specific Treatment ◽

Kidney Injury ◽

Length Of Hospital Stay ◽

Adjunctive Treatment ◽

Adjunct Treatment ◽

Propolis Extract ◽

Blinded Manner ◽

Double Blinded ◽

Brazilian Green Propolis

Abstract Background The 2019 coronavirus disease (COVID-19) pandemic continues to spread and affects large numbers of people with unprecedented impacts. To date, there is no consensus on a specific treatment. Experimental evidence has already been obtained for use of the standardized extract of Brazilian green propolis (EPP-AF) against viral targets, and clinical rationality has been demonstrated for testing this extract as an adjunct to treatment in patients affected by COVID-19. The BeeCovid2 study is once again assessing EPP-AF in hospitalized patients with coronavirus infection. Methods BeeCovid2 is a randomized, double-blinded, placebo-controlled clinical study being conducted in Brazil to provide further evidence on the effectiveness of standardized green propolis extract as an adjunctive treatment for adults hospitalized with COVID-19. Adults hospitalized with COVID-19 with respiratory symptoms for less than 14 days who are not on invasive oxygen therapy are eligible. Enrolled patients are randomized at a 1:1 ratio to receive placebo or standardized propolis extract (900 mg/day) for 10 days. The study treatments are administered in a double-blinded manner, and patients are followed for 28 days. The primary outcome is the length of hospital stay. Secondary outcomes include the need for mechanical ventilation, the rate of acute kidney injury, the need for renal replacement therapy, the requirement for vasoactive drugs, the use of an intra-aortic balloon pump (IABP), and the use of extracorporeal membrane oxygenation (ECMO). Discussion This trial is very useful and will provide more data on the effectiveness of using the standardized Brazilian green propolis extract as an adjunctive treatment in association with standard care in adults hospitalized with moderate to severe acute COVID-19. Trial registration: ClinicalTrials.gov NCT04800224. Registered on March 16, 2021.

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