Axillary vein as an alternative venous access site for VV-ECMO cannulation: a case report.

BACKGROUND: Ultrasound-guided percutaneous axillary vein cannulation can reduce cannulation failure and mechanical complications, is as safe and effective as internal jugular vein cannulation, and is superior to subclavian vein cannulation using landmark technique. As far, reports of venovenous extracorporeal membrane oxygenation (VV-ECMO) with percutaneous axillary vein cannulation are rare. CASE PRESENTATION: A 64-year-old man presenting with dyspnea and chest tightness after aspirating sewage was admitted to the emergency department. Computed tomography (CT) showed diffuse exudation of both lungs and arterial blood gas analysis showed an oxygenation index of 86. He was diagnosed with aspiration pneumonia-induced acute respiratory distress syndrome (ARDS) and intubated for deteriorated oxygenation. Despite the combination therapy of protective mechanical ventilation and prone position, the patient's oxygenation deteriorated further, accompanied with multiple organ dysfunction syndrome, which indicated the requirement of support with VV-ECMO. However, vascular ultrasound detected multiple thrombus within bilateral internal jugular veins. As an alternative, right axillary vein was chosen as the access site of return cannula. Subsequently, femoral-axillary VV-ECMO was successfully implemented under the ultrasound guidance, and the patient's oxygenation was significantly improved. Unfortunately, the patient died of hyperkalemia-induced ventricular fibrillation after 36 h of VV-ECMO running. Despite the poor prognosis, the blood flow during ECMO run was stable, and we observed no bleeding complication, vascular injury, or venous return disorder. CONCLUSIONS: Axillary vein is a feasible alternative access site of return cannula for VV-ECMO if internal jugular vein access were unavailable.

Ultrasound-Guided Venous Axillary Access Versus Standard Fluoroscopic Technique for Cardiac Lead Implantation: ZEROFLUOROAXI Randomized Trial.

BACKGROUND: Axillary vein puncture (AVP) and cephalic vein surgical cutdown are recommended in international guidelines because of their low risk of pneumothorax and chronic lead complications. Directly visualizing and puncturing the axillary vein under ultrasound guidance reduces radiation exposure, provides direct needle visualization, and lowers periprocedural complications. Our hypothesis is that ultrasound-guided axillary access is safer and more feasible than the standard fluoroscopic technique. OBJECTIVES: The purpose of this study was to assess the efficacy and safety of ultrasound-guided axillary venous access during cardiac lead implantation for pacemakers (PMs) and implantable cardioverter-defibrillator (ICD) implantations. METHODS: Patients were randomized in a 1:1 fashion to either axillary venous access under fluoroscopic guidance or ultrasound-guided axillary venous access. The composite outcome, including pneumothorax, hemothorax, inadvertent arterial puncture, pocket hematoma, pocket infection, lead dislodgement, and death, was evaluated 30 days after implantation. RESULTS: We randomized 270 patients into 2 groups: the standard group for fluoroguided AVP (n = 134) and the experimental group for ultrasound-guided AVP (n = 136). No disparities in baseline characteristics were observed between the groups. The median age of the patients was 81 years, with women comprising 41% of the population. The majority of patients received single- and dual-chamber PMs (87% vs 88%; P = 1.00), and slightly over 10% in both groups received ICDs (13% vs 12%; P = 0.85). In total, we placed 357 leads in PMs and 48 leads in ICDs. Among these, 295 leads were inserted via axillary vein access and 110 via cephalic vein access. Notably, the subclavian vein was never used as a vascular access. The composite outcome was lower in the ultrasound group according to intention-to-treat analysis (OR: 0.55; 95% CI: 0.31-0.99; P = 0.034). The main difference within the composite outcome was the lower incidence of inadvertent axillary arterial puncture in the experimental group (17% vs 6%; P = 0.004). The ultrasound group also exhibited lower total procedural x-ray exposure (10,344 µGy × cm2 vs 7,119 µGy × cm2; P = 0.002) while achieving the same rate of success at the first attempt (61% vs 69%; P = 0.375). CONCLUSIONS: Ultrasound-guided AVP is safer than the fluoroscopy-guided approach because it achieves the same rate of acute success while maintaining low total procedural radiation exposure. Ultrasound AVP should be considered the optimal venous access method for cardiac lead implantation. (Ultrasound Guided Axillary Access vs Standard Fluoroscopic Technique for Cardiac Lead Implantation [ZEROFLUOROAXI]; NCT05101720).

Intra-pocket ultrasound-guided axillary vein puncture vs. cephalic vein cutdown for cardiac electronic device implantation: the ACCESS trial.

BACKGROUND AND AIMS: Intra-pocket ultrasound-guided axillary vein puncture (IPUS-AVP) for venous access in implantation of transvenous cardiac implantable electronic devices (CIED) is uncommon due to the lack of clinical evidence supporting this technique. This study investigated the efficacy and early complications of IPUS-AVP compared to the standard method using cephalic vein cutdown (CVC) for CIED implantation. METHODS: ACCESS was an investigator-led, interventional, randomized (1:1 ratio), monocentric, controlled superiority trial. A total of 200 patients undergoing CIED implantation were randomized to IPUS-AVP (n = 101) or CVC (n = 99) as a first assigned route. The primary endpoint was the success rate of insertion of all leads using the first assigned venous access technique. The secondary endpoints were time to venous access, total procedure duration, fluoroscopy time, X-ray exposure, and complications. Complications were monitored during a follow-up period of three months after procedure. RESULTS: IPUS-AVP was significantly superior to CVC for the primary endpoint with 100 (99.0%) vs. 86 (86.9%) procedural successes (P = .001). Cephalic vein cutdown followed by subclavian vein puncture was successful in a total of 95 (96.0%) patients, P = .21 vs. IPUS-AVP. All secondary endpoints were also significantly improved in the IPUS-AVP group with reduction in time to venous access [3.4 vs. 10.6 min, geometric mean ratio (GMR) 0.32 (95% confidence interval, CI, 0.28-0.36), P < .001], total procedure duration [33.8 vs. 46.9 min, GMR 0.72 (95% CI 0.67-0.78), P < .001], fluoroscopy time [2.4 vs. 3.3 min, GMR 0.74 (95% CI 0.63-0.86), P < .001], and X-ray exposure [1083 vs. 1423 mGy.cm², GMR 0.76 (95% CI 0.62-0.93), P = .009]. There was no significant difference in complication rates between groups (P = .68). CONCLUSIONS: IPUS-AVP is superior to CVC in terms of success rate, time to venous access, procedure duration, and radiation exposure. Complication rates were similar between the two groups. Intra-pocket ultrasound-guided axillary vein puncture should be a recommended venous access technique for CIED implantation.

A surgical method to be reminded for the treatment of symptomatic ipsilateral central venous occlusions in patients with hemodialysis access: Axillo-axillary venous bypass case report and review of the literature.

BACKGROUND: In this case report, we present two chronic hemodialysis patients with upper extremity swelling due to central venous occlusions together with their clinical presentation, surgical management and brief review of the literature. METHODS: The first patient who was a 63-year-old female patient with a history of multiple bilateral arteriovenous fistulas (AVFs) was referred to our clinic. Physical examination demonstrated a functioning right brachio-cephalic AVF, with severe edema of the right arm, dilated venous collaterals, facial edema, and unilateral breast enlargement. In her history, multiple ipsilateral subclavian venous catheterizations were present for sustaining temporary hemodialysis access. The second patient was a 47-year-old male with a history of failed renal transplant, CABG surgery, multiple AV fistula procedures from both extremities, leg amputation caused by peripheral arterial disease, and decreased myocardial functions. He was receiving 3/7 hemodialysis and admitted to our clinic with right arm edema, accompanied by pain, stiffness, and skin hyperpigmentation symptoms ipsilateral to a functioning brachio-basilic AVF. He was not able to flex his arms, elbow, or wrist due to severe edema. RESULTS: Venography revealed right subclavian vein stenosis with patent contralateral central veins in the first patient. She underwent percutaneous transluminal angioplasty (PTA) twice with subsequent re-occlusions. After failed attempts of PTA, the patient was scheduled for axillo-axillary venous bypass in order to preserve the AV access function. In second patient, venography revealed right subclavian vein occlusion caused secondary to the subclavian venous catheters. Previous attempts for percutaneously crossing the chronic subclavian lesion failed multiple times by different centers. Hence, the patient was scheduled for axillo-axillary venous bypass surgery. CONCLUSION: In case of chronic venous occlusions, endovascular procedures may be ineffective. Since preserving the vascular access function is crucial in this particular patient population, venous bypass procedures should be kept in mind as an alternative for central venous reconstruction, before deciding on ligation and relocation of the AVF.

Axillary vein thrombosis 30 h after caesarean section: a case report and literature review.

BACKGROUND: Axillary vein thrombosis is a very rare disorder. However, a case of axillary vein thrombosis shortly after caesarean section has not been reported previously. We report a case of axillary vein thrombosis 30 h after caesarean section due to an unidentified aetiology. CASE: A 37-year-old multiparous woman developed swelling and pain of the forearm and hand 30 h after undergoing a caesarean section. Doppler ultrasonography revealed a 14.9 mm × 5.3 mm thrombosis in the left axillary vein although a prophylaxis of anticoagulation was administrated. After an adjusted-dose of low-molecular-weight heparin (LMWH) was administered, the patient recovered and was discharged. CONCLUSION: Obstetricians should be fully aware of the possibility of upper extremity deep vein thrombosis (DVT) despite its rarity, especially after the surgery. Lying in the lateral decubitus position for long periods postoperatively should be avoided as much as possible.

Single center experience with ultrasound guided axillary vein port placement.

PURPOSE: To retrospectively review a single institution experience of ultrasound guided axillary vein port placement. METHODS: In this retrospective study, a patient list was generated after searching our internal database from 1/1/2012 to 10/1/2018. Patients who had undergone axillary vein port placement were included. Chart review was performed to confirm approach, laterality and to gather demographic data, clinical indications, technical outcomes, and complications. Descriptive statistics were used to analyze this cohort. Chi-square statistics were used to compare outcomes by laterality. RESULTS: Three hundred seven patients (51% female) with an average age of 58 years were included. The port was placed via the right axillary vein in 85% (261/307), predominantly for the indication of chemotherapy access (296/307). Technical success was achieved in all 307 cases. Peri procedural complications occurred in 1% (4/307) of cases and included port malpositioning requiring replacement and a case of port pocket hematoma. Post procedural complications including deep vein thrombosis and port malfunction occurred in 17% (52/307) of cases and port removal as a result of complication occurred in 9% (29/307) of cases. CONCLUSIONS: Ultrasound guided placement of an axillary port is a safe procedure to perform and demonstrates good clinical outcomes.

Conversion of Arterio-Venous Access of Hemodialysis to Arterio-Arterial Access for Treatment of Venous hypertension with Central Venous Occlusion.

This report describes conversion of arterio-venous graft or fistula to arterio-arterial vascular access as a new surgical treatment option for central venous occlusion. It starts with control of the axillary vein and the synthetic graft or superficialized vein proximally, the suture line of venous anastomosis is closed and end-to-side anastomosis of the synthetic graft or vein to the brachial artery (BA) is done, then ligation of the BA distal to the anastomosis is done. Now the blood flow is directed through synthetic graft or vein from proximal to distal BA that can be used as arterio-arterial vascular access for hemodialysis.

Late Basilic Vein Superficialization Combined with Revision Using Distal Inflow (RUDI) Operation to Treat a Symptomatic High Flow Fistula.

BACKGROUND: Vascular access (VA)-related high flows (HF) are common with brachial artery based fistulas. Flow-reduction procedures are indicated in symptomatic patients or asymptomatic ones with flows >2 L/min. However concomitant issues increase their complexity. We describe a case of a patient suffering congestive heart failure as a result of HF brachial-basilic fistula >3 L/min. A simultaneous late basilic vein transposition and revision using distal inflow (RUDI) was performed. METHODS: A large diameter untransposed arterialized basilic vein was carefully and completely mobilized up to the proximal upper arm. After harvesting an autologous great saphenous vein (GSV) segment, a new inflow anastomosis was performed in the proximal ulnar artery. At the final stage, and after tunneling the mobilizing basilic vein in a subcutaneous semicircular configuration, an end-to-end anastomosis joining the two stumps (basilic vein outflow portion and GSV inflow arterial portion) was performed. A decision-making process in order to reach this complex option is discussed. Results Access flow and cardiac output were greatly attenuated following our approach. After a mean follow-up of 9 months no VA complications were observed, with flow still detected below 2 L/min. All cardiac symptoms and ultrasound investigations improved. CONCLUSION: Multiple VA issues including HF pose a risk for abandonment and a challenge for the vascular surgeon. An effort toward increasing the "upper extremity life span" is advised.

Axillary vein access for antiarrhythmic cardiac device implantation: a literature review.

The current narrative review provides an update of available knowledge on venous access techniques for cardiac implantable electronic device implantation, with a focus on axillary vein puncture. Lower procedure-related and lead-related complications have been reported with extrathoracic vein puncture techniques compared with intrathoracic accesses. In particular, extrathoracic lead access through the axillary vein seems to be associated with lower complication incidence than subclavian vein puncture and higher success rate than cephalic vein cutdown. In literature, many techniques have been described for axillary vein access. The use of contrast venography-guided puncture has facilitated the diffusion of the axillary vein approach for device implantation. Venography may be particularly useful in specific demographic and clinical device implantation contexts. Ultrasound-guided or microwire-guided vascular access for lead positioning can be considered a valid alternative to venography, although current applications for axillary vein puncture need further evaluations.

A Rare Case of Dysplastic Axillary Artery Aneurysm Associated with Arteriovenous Malformation.

BACKGROUND: Axillary artery aneurysms are rare conditions, and their causes are various. They can determine severe complications, so the treatment is extremely important. METHODS: We report the case of a young man affected by a saccular axillary artery aneurysm associated with intramuscular arteriovenous malformation, without symptoms except for the presence of a pulsatile mass. Duplex scan and computed tomography scan have been essential for a correct diagnosis and planning of the treatment. At first, the patient was submitted to coil embolization of an efferent vessel, and then he was treated surgically through ligation and detachment of the aneurysm and replacement of part of the axillary artery with a Dacron graft (Vascutek, Inchinnan, Renfrewshire, Scotland, UK). RESULTS: Follow-up at 1 and 6 months revealed normal patency of the axillary arterty and the prosthetic graft with complete exclusion and thrombosis of the aneurysm sac.No sensitive nor motor deficit were observed. CONCLUSIONS: Aneurysms of the axillary artery associated with intramuscular arteriovenous malformations are very rare, but have to be suspected. The treatment is challenging and can be surgical, endovascular, or hybrid, based on the patient's conditions and aneurysm's anatomical features.

The New Surface Landmarks for Blind Axillary Vein Puncture.

OBJECTIVE: To compare the efficacy of blind axillary vein puncture utilizing the new surface landmarks for the subclavian method. METHODS: This prospective and randomized study was performed at two cardiology medical centers in East China. Five hundred thirty-eight patients indicated to undergo left-sided pacemaker or implantable cardioverter defibrillator implantation were enrolled, 272 patients under the axillary access and 266 patients under the subclavian approach. A new superficial landmark was used for the axillary venous approach, whereas conventional landmarks were used for the subclavian venous approach. We measured lead placement time and X-ray time from vein puncture until all leads were placed in superior vena cava. Meanwhile, the rate of success of lead placement and the type and incidence of complications were compared between the two groups. RESULTS: There were no significant differences between the two groups in baseline characteristics or number of leads implanted. There were high success rates for both strategies (98.6% [494/501] vs. 98.4% [479/487], P=0.752) and similar complication rates (14% [38/272] vs. 15% [40/266], P=0.702). Six cases in the control group developed subclavian venous crush syndrome and five had pneumothorax, while neither pneumothorax nor subclavian venous crush syndrome was observed in the experimental group. CONCLUSION: We have developed a new blind approach to cannulate the axillary vein, which is as effective as the subclavian access, safer than that, and also allows to get this vein without the guidance of fluoroscopy, contrast, or echography.

The new surface landmarks for blind axillary vein puncture

Abstract Objective: To compare the efficacy of blind axillary vein puncture utilizing the new surface landmarks for the subclavian method. Methods: This prospective and randomized study was performed at two cardiology medical centers in East China. Five hundred thirty-eight patients indicated to undergo left-sided pacemaker or implantable cardioverter defibrillator implantation were enrolled, 272 patients under the axillary access and 266 patients under the subclavian approach. A new superficial landmark was used for the axillary venous approach, whereas conventional landmarks were used for the subclavian venous approach. We measured lead placement time and X-ray time from vein puncture until all leads were placed in superior vena cava. Meanwhile, the rate of success of lead placement and the type and incidence of complications were compared between the two groups. Results: There were no significant differences between the two groups in baseline characteristics or number of leads implanted. There were high success rates for both strategies (98.6% [494/501] vs. 98.4% [479/487], P=0.752) and similar complication rates (14% [38/272] vs. 15% [40/266], P=0.702). Six cases in the control group developed subclavian venous crush syndrome and five had pneumothorax, while neither pneumothorax nor subclavian venous crush syndrome was observed in the experimental group. Conclusion: We have developed a new blind approach to cannulate the axillary vein, which is as effective as the subclavian access, safer than that, and also allows to get this vein without the guidance of fluoroscopy, contrast, or echography.

Comparison of comfort and complications in breast cancer patients of implantable venous access port (IVAP) with ultrasound guided internal jugular vein (IJV) and axillary vein/subclavian vein (AxV/SCV) puncture: a randomized controlled study protocol.

BACKGROUND: Internal jugular vein (IJV) and axillary vein/subclavian vein (AxV/SCV) are commonly used for implantable venous access port (IVAP) implantation in breast cancer (BC) patients with chemotherapy. Previous studies focused on complications between these different approaches and ignored patient comfort. In this study, we aim to compare patient comfort between IJV and AxV/SCV approaches, as well as surgery duration and complications. METHODS: This is a single-center prospective randomized controlled clinical trial. A total of 200 patients diagnosed with invasive BC will be enrolled in this study. After signing written informed consent, patients schedule to undergo IVAP implantation will be randomized at a 1:1 ratio to receive central venous catheters (CVC) with either IJV or AxV/SCV approaches. Baseline as well as demographic data and procedure time of port implantation will be recorded. All patients will receive assessment of comfort with a comfort scale table at days 1, 2 and 7 after implantation surgery. Patients will be followed up and complications will be recorded until devices are removed at the end of the treatment period, or in case of complications. Patient comfort, procedure time of implantation and complications will be compared and analyzed between these two arms. DISCUSSION: To the best of our knowledge, this is the first study to compare patient comfort as primary outcome measure between IJV and AxV/SCV puncture. This study will further confirm the benefits of ultrasound guidance and may provide a better choice of IVAP implantation for BC patients. TRIAL REGISTRATION: This study has been registered at Chinese Clinical Trial Registry (ChiCTR, www. chictr.org.cn) and Chinese Ethics Committee of Registering Clinical Trials (No. ChiCTR2000034986).

Axillary vein puncture guided by ultrasound vs cephalic vein dissection in pacemaker and defibrillator implant: A multicenter randomized clinical trial.

BACKGROUND: Axillary vein puncture guided by ultrasound (US-Ax) has emerged as a valid alternative access route to pacemaker and defibrillator lead insertion. OBJECTIVE: The purpose of this study was to evaluate whether US-Ax compared to cephalic vein dissection (CV) improves success and early complications in pacemaker or defibrillator implant. METHODS: This prospective, multicenter clinical trial included 88 adult patients randomized 1:1 to US-Ax (n = 44) or CV (n = 44). All procedures were performed by operators with no previous experience in axillary approach. Primary endpoint was defined as success rate. Secondary endpoints were venous access site change, time to obtain venous access, total procedural time, and early complication rate. Analyses were performed using the intention-to-treat principle. RESULTS: Median age was 70.5 years (58.2-79.7), and 60.2% were male. For the primary outcome, a higher success rate was observed in the axillary group (97.7% vs 54.5%; P <.001), as well as a lower rate of venous access site change (2.3% vs 40.9%; P <.001) and shorter time to obtain venous access (5 vs 15 minutes; P <.001) and procedural time (40 vs 51 minutes; P = .010), with no difference in complication rate (2.3% vs 11.4%; P =.20). In multivariate analysis, US-Ax (P <.001), single-chamber device (P = .015), and body mass index (P = .015) were independent predictors of overall success. CONCLUSION: This is the first randomized trial comparing self-learned US-Ax to CV in cardiac lead implantation. Our results indicate that the axillary approach was superior in terms of success rate, time to obtain venous access and procedural time, with similar complication rate.

Sonographic visualization and cannulation of the axillary vein in two arm positions during mechanical ventilation: A randomized trial.

BACKGROUND: Abduction of the arm has been used for ultrasound-guided infraclavicular axillary vein cannulation. We evaluated the influence of arm position on sonographic visualization and cannulation of the axillary vein in patients receiving mechanical ventilation. METHODS: Sixty patients scheduled to undergo surgery under general anaesthesia with controlled mechanical ventilation were included in this prospective randomized study. The depth, size and distance of axillary vein to the pleura were recorded at three points: Point A, the most proximal part of the axillary vein visualized with adduction; Point A', Point A in abduction; and Point B, the most proximal part of axillary vein visualized in abduction. Cephalic movement of the clavicle at Point A' and the distance between Point A and Point B were noted. In Group A, cannulation was performed at Point A in the adducted arm and at Point B with the abducted arm in Group B after randomization. RESULTS: Abduction moved the clavicle cephalad by 2.2 ± 0.6 cm and increased sonographic visualization of the axillary vein by 2.2 ± 0.5 cm in length, when compared with adduction. The distance from the vein to pleura was higher in Point A' (p < 0.001). No differences were found during cannulation in terms of first-pass success rate or number of attempts. CONCLUSION: Abducted position moved the clavicle cephalad and allowed sonographic visualization of infraclavicular axillary vein approximately 2 cm more proximally than with the adducted arm, with a comparable rate of cannulation success.

Dynamic variation of the axillary veins due to intrathoracic pressure changes: A prospective sonographic study.

INTRODUCTION: The ultrasound-guided axillary vein is becoming a compulsory alternative vessel for central venous catheterization and the anatomical position offers several potential advantages over blind, subclavian vein techniques. OBJECTIVE: To determine the degree of dynamic variation of the axillary vein size measured by ultrasound prior to the induction of general anesthesia and after starting controlled mechanical ventilation. DESIGN: Prospective, observational study. METHODS: One hundred ten patients undergoing elective surgery were enrolled and classified according to sex, age, and body mass index. Two-dimensional cross-sectional vein diameter, area, and mean flow velocity were performed using ultrasound on both the left and right axillary veins of each subject before and after induction of anesthesia. RESULTS: There was statistically significant evidence showing that the axillary vein area increases when patients are mechanically ventilated. When considering venous flow velocity as a primary outcome, velocity decreased after patients moved from spontaneous to mechanical ventilation (coefficient = -0.267), but this relationship failed to achieve statistical significance (t = -1.355, p = 0.179). CONCLUSIONS: Anatomical variations in depth and diameter as well as the collapsibility due to intrathoracic pressures changes represent common challenges that face clinicians during central venous catheterization of the axillary vein. A noteworthy increase in vessel size as patients transition from spontaneous to mechanical ventilation may theoretically improve first-pass cannulation success with practitioners skilled in both ultrasound and procedure. As a result, placing a centrally inserted central catheter after the induction of anesthesia may be beneficial.

Fluoroscopy-guided axillary vein access vs cephalic vein access in pacemaker and defibrillator implantation: Randomized clinical trial of efficacy and safety.

INTRODUCTION: The most widespread venous sites of access for implantation intravenous implantable cardiac electronic device (CIED) are the cephalic and subclavian vein. Fluoroscopy-guided axillary venous access is an alternative, but efficacy and safety have not been studied under equal conditions. The aim of the present study is to compare the efficacy and safety of fluoroscopy-guided axillary vs cephalic vein access in CIED implant. METHODS AND RESULTS: Two hundred and forty patients were randomized to receive CIED implantation by the fluoroscopy-guided axillary vein access vs cephalic vein access. The implantation success, the procedure times and the complications were recorded. A comparison of the results of operators was made. The success rate of the randomized venous access was superior in the axillary group than in cephalic (98.3% vs 76.7%, P < .001). Time to access (6.8 ± 3.1 minute vs 13.1 ± 5.8 minutes, P < .001) and implantation duration was significantly shorter in the axillary group than in the cephalic group (42.3 ± 11.6 minutes vs 50.5 ± 13.3 minutes, P < .001). There was no difference in the incidence of complication and inter-operator success rate, complications rate and time to access. CONCLUSION: The fluoroscopy-guided axillary venous access is safe and has a better success rate and faster execution time compared with the cephalic vein access. When the results were compared among the study operators, neither in the axillary nor in the cephalic group there were differences in the success rate, the complication rate, and the time to access. TRIAL REGISTRATION: www.clinicaltrials.gov, NCT03860090.