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1.
Lung ; 200(6): 737-745, 2022 12.
Article in English | MEDLINE | ID: mdl-36216921

ABSTRACT

PURPOSE: Tissue acquisition in lung cancer is vital for multiple reasons. Primary reasons reported for molecular testing failure in lung cancer biopsy specimens include insufficient amount of tumor cells provided and inadequate tissue quality. Robotic bronchoscopy is a new tool enabling peripheral pulmonary lesion sampling; however, diagnostic yield remains imperfect possibly due to the location of nodules adjacent to or outside of the airway. The 1.1-mm cryoprobe is a novel diagnostic tool and accesses tissue in a 360-degree manner, thus potentially sampling eccentric/adjacent lesions. This study examines the diagnostic yield of the cryoprobe compared to standard needle aspiration and forceps biopsy. It additionally evaluates yield for molecular markers in cases of lung cancer. METHODS: This is a retrospective analysis of 112 patients with 120 peripheral pulmonary lesions biopsied via robotic bronchoscopy using needle aspirate, forceps, and cryobiopsy. RESULTS: The overall diagnostic yield was 90%. Nearly 18% of diagnoses were made exclusively from the cryobiopsy sample. Molecular analysis was adequate on all cryobiopsy samples sent. Digital imaging software confirmed an increase in quantity and quality of samples taken via cryobiopsy compared to needle aspirate and traditional forceps biopsy. CONCLUSION: Using the 1.1-mm cryoprobe to biopsy PPN combined with the Ion robotic bronchoscopy system is safe, feasible, and provides more diagnostic tissue than needle aspirates or traditional forceps biopsies. The combination of cryobiopsy with robotic-assisted bronchoscopy increased diagnostic yield, likely due to its 360-degree tissue acquisition which is beneficial when targeting extraluminal lesions adjacent to the airway.


Subject(s)
Cryosurgery , Lung Neoplasms , Robotic Surgical Procedures , Humans , Retrospective Studies , Bronchoscopy/methods , Lung/pathology , Biopsy/methods , Lung Neoplasms/pathology
2.
Semin Respir Crit Care Med ; 43(4): 492-502, 2022 08.
Article in English | MEDLINE | ID: mdl-35714628

ABSTRACT

Tracheostomy is a procedure commonly performed in intensive care units (ICU) for patients who are unable to be weaned from mechanical ventilation. Both percutaneous and surgical techniques have been validated and are chosen based on the local expertise available. A primary advantage to the percutaneous technique is the ability to perform this procedure in the ICU without transporting the patient to a procedure suite or operating room; this has become particularly important with the novel coronavirus disease 2019 (COVID-19) pandemic. An additional advantage is the ability to perform both the tracheostomy and the gastrostomy tube placement, if needed, during the same anesthetic episode. This decreases the need for additional sedation, interruption of anticoagulation, repeat transfusion, and coordination of care between multiple services. In the context of COVID-19, combined tracheostomy and gastrostomy placement exposes less health care providers overall and minimizes transportation needs.


Subject(s)
COVID-19 , Pulmonary Medicine , Esophagus , Gastrostomy/methods , Humans , Tracheostomy/methods
3.
Respir Med ; 200: 106913, 2022.
Article in English | MEDLINE | ID: mdl-35724519

ABSTRACT

INTRODUCTION: Transbronchial lung cryobiopsy (TBLC) has emerged as a promising alternative to surgical lung biopsy for the diagnosis of interstitial lung disease. However, uncertainty remains regarding its overall complications due to a lack of procedural standardization including the size of cryoprobe utilized. METHODS: This is a prospective cohort study of a protocolized transbronchial cryobiopsy program utilizing a 2.4 mm cryoprobe. 201 consecutive subjects were enrolled at a single academic center. RESULTS: The average biopsy size was 106.2 ± 39.3 mm2. Complications included a total pneumothorax rate of 4.9% with 3.5% undergoing chest tube placement. Severe bleeding defined by the Nashville Working Group occurred in 0.5% of cases. There were no deaths at 30-days. DISCUSSION: A protocolized transbronchial cryobiopsy program utilizing a 2.4 mm cryoprobe in can achieve a high diagnostic yield with a favorable safety profile.


Subject(s)
Bronchoscopy , Lung Diseases, Interstitial , Biopsy/adverse effects , Bronchoscopy/adverse effects , Humans , Lung/pathology , Lung Diseases, Interstitial/diagnosis , Lung Diseases, Interstitial/pathology , Prospective Studies
4.
Respiration ; 101(7): 666-674, 2022.
Article in English | MEDLINE | ID: mdl-35316812

ABSTRACT

BACKGROUND: Malignant central airway obstruction (CAO) is a debilitating complication of primary lung cancer and pulmonary metastases. Therapeutic bronchoscopy is used to palliate symptoms and/or bridge to further therapy. Microwave ablation (MWA) heats tissue by creating an electromagnetic field around an ablation device. We present a pilot study utilizing endobronchial MWA via flexible bronchoscopy as a novel modality for the management of malignant CAO. METHODS: Therapeutic bronchoscopy with a flexible MWA probe was performed in 8 cases. We reviewed tumor size, previous ablative techniques, number of applications, ablation time, amount of energy delivered, rate of successful recanalization, complications, and 30-day follow-up. RESULTS: Successful airway recanalization was achieved in all cases. No complications were noted. In 1 case, tumor in-growth within a silicone stent was ablated with no damage to the stent. DISCUSSION: Endobronchial MWA is a novel technique for tumor destruction while maintaining an airway axis. The oven effect and air gap around a tumor allow for safe and effective tissue devitalization and hemostasis without a thermal effect on structures surrounding the airway.


Subject(s)
Airway Obstruction , Lung Neoplasms , Airway Obstruction/etiology , Airway Obstruction/surgery , Bronchoscopy/methods , Humans , Lung Neoplasms/complications , Lung Neoplasms/surgery , Microwaves/therapeutic use , Pilot Projects
5.
Curr Opin Pulm Med ; 28(1): 37-44, 2022 01 01.
Article in English | MEDLINE | ID: mdl-34789649

ABSTRACT

PURPOSE OF REVIEW: To describe the emerging field of robotic bronchoscopy within advanced diagnostic bronchoscopy. We review the literature available for these two novel platforms to highlight their differences and discuss the impact on future directions. RECENT FINDINGS: There are two distinct technologies both known as robotic bronchoscopy. The Monarch robotic-assisted bronchoscopy is based on electromagnetic guidance whereas the Ion robotic-assisted bronchoscopy is founded on shape sensing technology. Although there is ongoing work to explore the capabilities of these systems, studies have shown that both are safe modalities. Furthermore, both hold promise to improve diagnostic yield and may eventually pave the way for therapeutic bronchoscopic ablation in the future. SUMMARY: Although both platforms fall under the umbrella term of robotic-assisted bronchoscopy, the Monarch and Ion systems are quite unique in their technology. Thus far, both have demonstrated safety, and early data shows promising results for improved diagnostic yield compared to previously advanced bronchoscopy modalities, especially when combined with advanced confirmatory imaging. Future directions may include bronchoscopic ablation of peripheral lesions given the stability and reach of these platforms.


Subject(s)
Lung Neoplasms , Pulmonary Medicine , Robotic Surgical Procedures , Bronchoscopy , Humans
6.
J Intensive Care Med ; 36(11): 1340-1346, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34424096

ABSTRACT

Background: A significant number of patients with severe respiratory failure related to COVID-19 require prolonged mechanical ventilation. Minimal data exists regarding the timing, safety, and efficacy of combined bedside percutaneous tracheostomy and endoscopy gastrostomy tube placement in these patients. The safety for healthcare providers is also in question. This study's objective was to evaluate the effectiveness and safety of combined bedside tracheostomy and gastrostomy tube placement in COVID-19 patients. Design and Methods: This is a single arm, prospective cohort study in patients with COVID-19 and acute respiratory failure requiring prolonged mechanical ventilation who underwent bedside tracheostomy and percutaneous endoscopic gastrostomy placement. Detailed clinical and procedural data were collected. Descriptive statistics were employed and time to event curves were estimated and plotted using the Kaplan Meier method for clinically relevant prespecified endpoints. Results: Among 58 patients, the median total intensive care unit (ICU) length of stay was 29 days (24.7-33.3) with a median of 10 days (6.3-13.7) postprocedure. Nearly 88% of patients were weaned from mechanical ventilation postprocedure at a median of 9 days (6-12); 94% of these were decannulated. Sixty-day mortality was 10.3%. Almost 90% of patients were discharged alive from the hospital. All procedures were done at bedside with no patient transfer required out of the ICU. A median of 3.0 healthcare personnel total were present in the room per procedure. Conclusion: This study shows that survival of critically ill COVID-19 patients after tracheostomy and gastrostomy was nearly 90%. The time-to-event curves are encouraging regarding time to weaning, downsizing, decannulation, and discharge. A combined procedure minimizes the risk of virus transmission to healthcare providers in addition to decreasing the number of anesthetic episodes, transfusions, and transfers patients must undergo. This approach should be considered in critically ill COVID-19 patients requiring prolonged mechanical ventilation.


Subject(s)
COVID-19 , Tracheostomy , Gastrostomy , Humans , Prospective Studies , SARS-CoV-2
7.
Respiration ; 100(6): 510-514, 2021.
Article in English | MEDLINE | ID: mdl-33784700

ABSTRACT

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has drastically affected hospital and operating room (OR) workflow around the world as well as trainee education. Many institutions have instituted mandatory preoperative SARS-CoV-2 PCR nasopharyngeal swab (NS) testing in patients who are low risk for COVID-19 prior to elective cases. This method, however, is challenging as the sensitivity, specificity, and overall reliability of testing remains unclear. OBJECTIVES: The objective of this study was to assess the concordance of a negative NS in low risk preoperative patients with lower airway bronchoalveolar lavage (BAL) specimens obtained from the same patients. METHODS: We prospectively sent intraoperative lower airway BAL samples collected within 48 h of a negative mandatory preoperative NS for SARS-CoV-2 PCR testing. All adult patients undergoing a scheduled bronchoscopic procedure for any reason were enrolled, including elective and nonelective cases. RESULTS: One-hundred eighty-nine patients were included. All BAL specimens were negative for SARS-CoV-2 indicative of 100% concordance between testing modalities. CONCLUSIONS: These results are promising and suggest that preoperative nasopharyngeal SARS-CoV-2 testing provides adequate screening to rule out active COVID-19 infection prior to OR cases in a population characterized as low risk by negative symptom screening. This information can be used for both pre-procedural screening and when reintroducing trainees into the workforce.


Subject(s)
Bronchoalveolar Lavage Fluid , COVID-19 Nucleic Acid Testing/methods , COVID-19/diagnosis , Carrier State/diagnosis , Nasopharynx , Adult , Aged , Aged, 80 and over , Bronchoalveolar Lavage , Bronchoscopy , Female , Humans , Male , Mass Screening , Middle Aged , Preoperative Care , Prospective Studies , Risk , Sensitivity and Specificity , Young Adult
8.
Respiration ; : 1-5, 2021 Feb 04.
Article in English | MEDLINE | ID: mdl-33540412

ABSTRACT

BACKGROUND: Argon plasma coagulation (APC) is a tool used in the management of tracheobronchial obstruction or bleeding. Complications include gas embolism which can cause devastating effects including hemodynamic instability, cardiac arrest, and stroke. Multiple theories as to how gas embolism occurs with APC have been postulated; however, none have identified the exact mechanism. OBJECTIVES: To identify the mechanism by which APC causes gas embolism in the tracheobronchial tree. METHODS: Using an explanted porcine tracheobronchial tree with lung parenchyma, the APC catheter was applied through noncontact and direct contact to the endobronchial airway mucosa via flexible bronchoscopy. This was done at multiple gas flow settings and pulse durations. Visual changes in the mucosa were photographed, videoed, and described. RESULTS: Gross evidence of submucosal gas transfer occurred when the APC catheter was in direct contact with the mucosa at all gas flow settings in all applications, despite using shorter pulse durations. Whenever the catheter was not in contact with the mucosa, there was no transfer of gas at any gas flow setting or pulse duration. CONCLUSIONS: Direct mucosal contact with the APC probe leads to submucosal gas deposition and is a likely mechanism for gas entry into the intravascular space. In reported cases of APC-associated gas embolism, presence of a vascularized endobronchial tumor may have increased the risk of gas tracking into the intravascular space. Care should be taken when applying APC during brisk bleeding or limited vision, as inadvertent mucosal contact may occur and could increase the risk of gas embolism.

9.
Respir Care ; 65(11): 1773-1783, 2020 11.
Article in English | MEDLINE | ID: mdl-32759372

ABSTRACT

The COVID-19 pandemic has profoundly affected health care delivery worldwide. A small yet significant number of patients with respiratory failure will require prolonged mechanical ventilation while recovering from the viral-induced injury. The majority of reports thus far have focused on the epidemiology, clinical factors, and acute care of these patients, with less attention given to the recovery phase and care of those patients requiring extended time on mechanical ventilation. In this paper, we review the procedures and methods to safely care for patients with COVID-19 who require tracheostomy, gastrostomy, weaning from mechanical ventilation, and final decannulation. The guiding principles consist of modifications in the methods of airway care to safely prevent iatrogenesis and to promote safety in patients severely affected by COVID-19, including mitigation of aerosol generation to minimize risk for health care workers.


Subject(s)
Coronavirus Infections , Device Removal/methods , Gastrostomy , Infection Control , Pandemics , Pneumonia, Viral , Tracheostomy , Ventilator Weaning/methods , Betacoronavirus , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/surgery , Coronavirus Infections/therapy , Critical Care/methods , Critical Care/standards , Gastrostomy/instrumentation , Gastrostomy/methods , Humans , Infection Control/instrumentation , Infection Control/methods , Infection Control/standards , Pneumonia, Viral/complications , Pneumonia, Viral/surgery , Pneumonia, Viral/therapy , Respiration, Artificial/methods , Risk Adjustment , SARS-CoV-2 , Tracheostomy/instrumentation , Tracheostomy/methods
11.
Chest ; 158(1): 393-400, 2020 07.
Article in English | MEDLINE | ID: mdl-32067944

ABSTRACT

BACKGROUND: Transbronchial lung biopsies are commonly performed for a variety of indications. Although generally well tolerated, complications such as bleeding do occur. Description of bleeding severity is crucial both clinically and in research trials; to date, there is no validated scale that is widely accepted for this purpose. Can a simple, reproducible tool for categorizing the severity of bleeding after transbronchial biopsy be created? METHODS: Using the modified Delphi method, an international group of bronchoscopists sought to create a new scale tailored to assess bleeding severity among patients undergoing flexible bronchoscopy with transbronchial lung biopsies. Cessation criteria were specified a priori and included reaching > 80% consensus among the experts or three rounds, whichever occurred first. RESULTS: Thirty-six expert bronchoscopists from eight countries, both in academic and community practice settings, participated in the creation of the scale. After the live meeting, two iterations were made. The second and final scale was vetted by all 36 participants, with a weighted average of 4.47/5; 53% were satisfied, and 47% were very satisfied. The panel reached a consensus and proposes the Nashville Bleeding Scale. CONCLUSIONS: The use of a simplified airway bleeding scale that can be applied at bedside is an important, necessary tool for categorizing the severity of bleeding. Uniformity in reporting clinically significant airway bleeding during bronchoscopic procedures will improve the quality of the information derived and could lead to standardization of management. In addition to transbronchial biopsies, this scale could also be applied to other bronchoscopic procedures, such as endobronchial biopsy or endobronchial ultrasound-guided needle aspiration.


Subject(s)
Biopsy/adverse effects , Blood Loss, Surgical , Bronchoscopy/adverse effects , Lung/pathology , Severity of Illness Index , Attitude of Health Personnel , Delphi Technique , Humans , Outcome Assessment, Health Care , Reproducibility of Results
12.
Chest ; 157(2): 446-453, 2020 02.
Article in English | MEDLINE | ID: mdl-31472155

ABSTRACT

Central airway obstruction (CAO) is associated with significant morbidity and increased mortality. Bronchoscopic electrosurgical and laser ablative tools have proven to be safe and effective instruments for the treatment of malignant CAO. Although therapeutic modalities such as electrocautery, argon plasma coagulation, and laser have been used for decades, additional tools including radiofrequency ablation catheters continue to be developed for the treatment of CAO. These modalities are considered safe in the hands of experienced operators, although serious complications can occur. This review describes various electrosurgical and laser therapy tools used for the treatment of malignant CAO along with the specific advantages and disadvantages of each device.


Subject(s)
Airway Obstruction/surgery , Argon Plasma Coagulation/methods , Bronchoscopy , Catheter Ablation/methods , Electrosurgery/methods , Laser Therapy/methods , Respiratory Tract Neoplasms/surgery , Airway Obstruction/etiology , Argon Plasma Coagulation/adverse effects , Argon Plasma Coagulation/economics , Bronchi , Catheter Ablation/adverse effects , Catheter Ablation/economics , Electrocoagulation/adverse effects , Electrocoagulation/economics , Electrocoagulation/methods , Electrosurgery/adverse effects , Electrosurgery/economics , Humans , Laser Therapy/adverse effects , Laser Therapy/economics , Neoplasms/complications , Neoplasms/surgery , Respiratory Tract Neoplasms/complications , Trachea
13.
J Thorac Imaging ; 34(4): 248-257, 2019 Jul.
Article in English | MEDLINE | ID: mdl-31145187

ABSTRACT

Chronic obstructive pulmonary disease is a condition characterized by progressive airflow limitation caused by airway and parenchymal inflammation. Current medical therapies, including bronchodilators, corticosteroids, and anti-inflammatory medications, have been shown to variably improve pulmonary function or quality of life without providing a long-term mortality benefit. Mortality benefits to therapy have been demonstrated in only 2 therapeutic interventions to date: long-term use of daily supplemental oxygen and surgical lung volume reduction (LVRS) for upper-lobe-predominant disease in patients with a low baseline exercise capacity. Newer bronchoscopic techniques for lung volume reduction (bLVR) have attracted interest from clinicians and researchers. To achieve successful results, these advanced therapies require an interdisciplinary approach between general and interventional pulmonologists and thoracic radiologists. In this article, we aim to review the latest interventional pulmonary techniques for treatment of chronic obstructive pulmonary disease with an emphasis on bLVR. We will review the bLVR preprocedure imaging evaluation, postprocedure imaging findings, and explore the potential benefits and risks of therapy based on the most recent clinical trial evidence.


Subject(s)
Bronchoscopy/methods , Pneumonectomy/methods , Pulmonary Disease, Chronic Obstructive/surgery , Humans , Lung/surgery
14.
Respirology ; 24(5): 453-458, 2019 05.
Article in English | MEDLINE | ID: mdl-30675961

ABSTRACT

BACKGROUND AND OBJECTIVE: Percutaneous lung biopsy for diagnostic sampling of peripheral lung nodules has been widely performed by interventional radiologists under computed tomography (CT) guidance. New technology allows pulmonologists to perform percutaneous lung biopsies using electromagnetic (EM) guided technology. With the adoption of this new technique, the safety, feasibility and diagnostic yield need to be explored. The goal of this study was to determine the safety, feasibility and diagnostic yield of EM-guided percutaneous lung biopsy performed by pulmonologists. METHODS: We conducted a retrospective, multicentre study of 129 EM-guided percutaneous lung biopsies that occurred between November 2013 and March 2017. The study consisted of seven academic and three community medical centres. RESULTS: The average age of participants was 65.6 years, BMI was 26.3 and 50.4% were females. The majority of lesions were in the right upper lobe (37.2%) and left upper lobe (31.8%). The mean size of the lesions was 27.31 mm and the average distance from the pleura was 13.2 mm. Practitioners averaged two fine-needle aspirates and five core biopsies per procedure. There were 23 (17.8%) pneumothoraces, of which 16 (12.4%) received small-bore chest tube placement. The diagnostic yield of percutaneous lung biopsy was 73.7%. When EM-guided bronchoscopic sampling was also performed during the same procedural encounter, the overall diagnostic yield increased to 81.1%. CONCLUSION: In this large multicentred series, the use of EM guidance for percutaneous lung biopsies was safe and feasible, with acceptable diagnostic yield in the hands of pulmonologists. A prospective multicentre trial to validate these findings is currently underway (NCT03338049).


Subject(s)
Biopsy/methods , Lung Neoplasms/pathology , Multiple Pulmonary Nodules/pathology , Pulmonary Medicine/methods , Adult , Aged , Aged, 80 and over , Biopsy/adverse effects , Biopsy, Fine-Needle/adverse effects , Biopsy, Large-Core Needle/adverse effects , Bronchoscopy , Electromagnetic Phenomena , Feasibility Studies , Female , Humans , Image-Guided Biopsy/adverse effects , Lung/pathology , Lung Neoplasms/diagnosis , Male , Middle Aged , Multiple Pulmonary Nodules/diagnosis , Pneumothorax/etiology , Retrospective Studies
15.
Semin Respir Crit Care Med ; 39(6): 731-746, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30641591

ABSTRACT

Benign central airway obstruction (CAO) is responsible for significant morbidity due to dyspnea and impaired quality of life. While iatrogenic causes, including stenosis after endotracheal intubation, tracheostomy tube placement, and surgery, account for the majority of cases of benign CAO, there are a multitude of other causes including infections, inflammatory disorders, extrinsic compression, benign endobronchial tumors, and tracheobronchomalacia. The approach to management depends on the underlying process responsible for the disorder and may include systemic therapy, endoscopic therapy, and surgery. In this review, we aim to provide a general overview of the presentation, evaluation, and management of nonmalignant CAO followed by a more in-depth review of several of the more common causes of this disorder.


Subject(s)
Airway Obstruction/etiology , Airway Obstruction/therapy , Laryngostenosis/diagnosis , Postoperative Complications/therapy , Tracheal Stenosis/diagnosis , Bronchoscopy/adverse effects , Humans , Intubation, Intratracheal/adverse effects , Laryngostenosis/therapy , Severity of Illness Index , Stents/adverse effects , Tomography, X-Ray Computed , Tracheal Stenosis/therapy , Tracheostomy/adverse effects
16.
Crit Care Med ; 45(3): e321-e325, 2017 Mar.
Article in English | MEDLINE | ID: mdl-27661862

ABSTRACT

OBJECTIVE: To report a case series of three patients with hepatitis C virus infection who all presented with severe type B lactic acidosis shortly after starting treatment with ombitasvir-paritaprevir-ritonavir-dasabuvir. DESIGN: Case series. SETTING: ICU. PATIENTS: Three patients, all who had HCV cirrhosis with mild hepatic impairment (Child-Pugh A) and had started taking ombitasvir-paritaprevir-ritonavir-dasabuvir within the preceding 2 weeks, presented with similar nonspecific symptoms of lethargy, fatigue, and nausea. All had elevated lactate levels at admission without evidence of hypovolemia, cardiogenic failure, or vasodilatory shock. INTERVENTIONS: All patients were given appropriate supportive intensive care for what was initially suspected to be sepsis, including a minimum of 30 mL/kg of IV fluids, infectious workup including blood cultures, broad-spectrum antibiotics, and mechanical ventilatory support. The first patient received continuous veno-venous hemofiltration. The second patient received hemodialysis. The third patient was initially started on hemodialysis despite high norepinephrine requirements and ultimately transitioned to continuous veno-venous hemofiltration. MEASUREMENTS AND MAIN RESULTS: The first patient died despite maximal intensive care. The second patient improved immediately upon starting hemodialysis and was extubated within 48 hours and discharged home. The third patient eventually became hypotensive and was treated with repeated sessions of renal replacement therapy. He ultimately was extubated and discharged home. The infectious workup was negative for all three patients, and antibiotics were discontinued after 2 days in the second and third patients. CONCLUSIONS: Ombitasvir-paritaprevir-ritonavir-dasabuvir may cause type B lactic acidosis. Further study is warranted to identify risk factors and elucidate the mechanisms of excessive lactate production.


Subject(s)
Acidosis, Lactic/chemically induced , Acidosis, Lactic/therapy , Antiviral Agents/adverse effects , Hepatitis C, Chronic/drug therapy , Macrocyclic Compounds/adverse effects , Ritonavir/adverse effects , Sulfonamides/adverse effects , Uracil/analogs & derivatives , 2-Naphthylamine , Anilides/adverse effects , Carbamates/adverse effects , Cyclopropanes , Drug Combinations , Female , Fluid Therapy , Hemofiltration , Hepatitis C, Chronic/complications , Humans , Lactams, Macrocyclic , Liver Cirrhosis/virology , Male , Middle Aged , Proline/analogs & derivatives , Renal Dialysis , Respiration, Artificial , Uracil/adverse effects , Valine
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