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1.
J Cereb Blood Flow Metab ; : 271678X241248228, 2024 Apr 13.
Artículo en Inglés | MEDLINE | ID: mdl-38613232

RESUMEN

The impact of physiological stressors on cerebral sympathetic nervous activity (SNA) remains controversial. We hypothesized that cerebral noradrenaline (NA) spillover, an index of cerebral SNA, would not change during both submaximal isometric handgrip (HG) exercise followed by a post-exercise circulatory occlusion (PECO), and supine dynamic cycling exercise. Twelve healthy participants (5 females) underwent simultaneous blood sampling from the right radial artery and right internal jugular vein. Right internal jugular vein blood flow was measured using Duplex ultrasound, and tritiated NA was infused through the participants' right superficial forearm vein. Heart rate was recorded via electrocardiogram and blood pressure was monitored using the right radial artery. Total NA spillover increased during HG (P = 0.049), PECO (P = 0.006), and moderate cycling exercise (P = 0.03) compared to rest. Cerebral NA spillover remained unchanged during isometric HG exercise (P = 0.36), PECO after the isometric HG exercise (P = 0.45), and during moderate cycling exercise (P = 0.94) compared to rest. These results indicate that transient increases in blood pressure during acute exercise involving both small and large muscle mass do not engage cerebral SNA in healthy humans. Our findings suggest that cerebral SNA may be non-obligatory for exercise-related cerebrovascular adjustments.

2.
Br J Anaesth ; 129(5): 659-669, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36184294

RESUMEN

BACKGROUND: Portal vein Doppler ultrasound pulsatility measured by transoesophageal echocardiography is a marker of the haemodynamic impact of venous congestion in cardiac surgery. We investigated whether the presence of abnormal portal vein flow pulsatility is associated with a longer duration of invasive life support and postoperative complications in high-risk patients. METHODS: In this multicentre cohort study, pulsed-wave Doppler ultrasound assessments of portal vein flow were performed during anaesthesia before initiation of cardiopulmonary bypass (before CPB) and after separation of cardiopulmonary bypass (after CPB). Abnormal pulsatility was defined as portal pulsatility fraction (PPF) ≥50% (PPF50). The primary outcome was the cumulative time in perioperative organ dysfunction (TPOD) requiring invasive life support during 28 days. Secondary outcomes included major postoperative complications. RESULTS: 373 patients, 71 (22.0%) had PPF50 before CPB and 77 (24.9%) after CPB. PPF50 was associated with longer duration of TPOD (median [inter-quartile range]; before CPB: 27 h [11-72] vs 19 h [8.5-42], P=0.02; after CPB: 27 h [11-61] vs 20 h [8-42], P=0.006). After adjusting for confounders, PPF50 before CPB showed significant association with TPOD. PPF50 after CPB was associated with a higher rate of major postoperative complications (36.4% vs 20.3%, P=0.006). CONCLUSIONS: Abnormal portal vein flow pulsatility before cardiopulmonary bypass was associated with longer duration of life support therapy after cardiac surgery in high-risk patients. Abnormal portal vein flow pulsatility after cardiopulmonary bypass separation was associated with a higher risk of major postoperative complications although this association was not independent of other factors. CLINICAL TRIAL REGISTRATION: NCT03656263.


Asunto(s)
Procedimientos Quirúrgicos Cardíacos , Vena Porta , Humanos , Vena Porta/diagnóstico por imagen , Estudios Prospectivos , Estudios de Cohortes , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Ultrasonografía Doppler , Complicaciones Posoperatorias/etiología
5.
Can J Anaesth ; 67(10): 1393-1404, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32440906

RESUMEN

Pulmonary complications are the most common clinical manifestations of coronavirus disease (COVID-19). From recent clinical observation, two phenotypes have emerged: a low elastance or L-type and a high elastance or H-type. Clinical presentation, pathophysiology, pulmonary mechanics, radiological and ultrasound findings of these two phenotypes are different. Consequently, the therapeutic approach also varies between the two. We propose a management algorithm that combines the respiratory rate and oxygenation index with bedside lung ultrasound examination and monitoring that could help determine earlier the requirement for intubation and other surveillance of COVID-19 patients with respiratory failure.


RéSUMé: Les complications pulmonaires du coronavirus (COVID-19) constituent ses manifestations cliniques les plus fréquentes. De récentes observations cliniques ont fait émerger deux phénotypes : le phénotype à élastance faible ou type L (low), et le phénotype à élastance élevée, ou type H (high). La présentation clinique, la physiopathologie, les mécanismes pulmonaires, ainsi que les observations radiologiques et échographiques de ces deux différents phénotypes sont différents. L'approche thérapeutique variera par conséquent selon le phénotype des patients atteints de COVID-19 souffrant d'insuffisance respiratoire.


Asunto(s)
Infecciones por Coronavirus/complicaciones , Pulmón/diagnóstico por imagen , Neumonía Viral/complicaciones , Insuficiencia Respiratoria/diagnóstico por imagen , Ultrasonografía , Enfermedad Aguda , Algoritmos , COVID-19 , Infecciones por Coronavirus/diagnóstico por imagen , Humanos , Pulmón/fisiopatología , Pulmón/virología , Oxígeno/metabolismo , Pandemias , Fenotipo , Neumonía Viral/diagnóstico por imagen , Sistemas de Atención de Punto , Insuficiencia Respiratoria/virología , Frecuencia Respiratoria/fisiología
7.
Can J Anaesth ; 67(3): 353-359, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31758491

RESUMEN

BACKGROUND: Ultrasound (US) examination of the eye can be used to detect and monitor elevated intracranial pressure (ICP) and its consequences. Elevated ICP is transmitted to the contiguous optic nerve and its sheath (dura mater), thus underlying the development of papilledema and a widened sheath diameter. The US measurement of the optic nerve sheath diameter (ONSD) has previously been validated to diagnose and monitor raised ICP. The occurrence of vitreous hemorrhage in association with subarachnoid hemorrhage (SAH)-i.e., Terson syndrome-can also be easily diagnosed using ophthalmic US. Because of its relevance in anesthesia and critical care, we describe how to perform the technique illustrated by two cases. CASE PRESENTATIONS: A 72-yr-old man with hydrocephalus secondary to a SAH developed raised ICP following the removal of an external ventricular drainage (EVD) system. Daily ONSD measurements using handheld US allowed us to diagnose and monitor the progression and resolution of the intracranial hypertension following the placement of a second EVD system. We also describe the steps used to obtain ONSD measurements during the ophthalmic US examination of a 53-yr-old woman who presented with a stage IV SAH with concomitant bilateral vitreous hemorrhages or Terson syndrome. CONCLUSION: Ophthalmic US using a handheld device to measure and monitor ONSD at the bedside is useful in diagnosing and monitoring the progression of intracranial hypertension following EVD removal in a patient with hydrocephalus secondary to SAH. Ophthalmic US can also be used to identify concomitant vitreous hemorrhage that is associated with a worse prognosis.


Asunto(s)
Hipertensión Intracraneal , Sistemas de Atención de Punto , Hemorragia Vítrea , Femenino , Humanos , Hipertensión Intracraneal/diagnóstico por imagen , Presión Intracraneal , Masculino , Estudios Prospectivos , Ultrasonografía , Hemorragia Vítrea/diagnóstico por imagen , Hemorragia Vítrea/etiología
8.
J Cardiothorac Surg ; 13(1): 98, 2018 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-30257688

RESUMEN

BACKGROUND: Diaphragmatic plication to help ventilation weaning of an adult obese patient after cardiac surgery is very uncommon. Diaphragm paralysis is usually treated with conservative measures and ventilator support, after which surgical management is considered after months of medical monitoring. CASE PRESENTATION: We report the case of a morbidly obese patient to whom ventilation weaning was unsuccessful following coronary artery bypass graft operation with mitral valve replacement. A de novo right hemidiaphragm elevation was seen on the chest X-ray. Diaphragmatic plication was performed promptly to treat severe respiratory insufficiency and generated favorable outcomes. CONCLUSIONS: Early diaphragmatic plication could be considered in the postoperative period of cardiothoracic surgery to facilitate management and ventilation weaning in the context of de novo diaphragm paralysis.


Asunto(s)
Procedimientos Quirúrgicos Cardíacos/efectos adversos , Diafragma/cirugía , Obesidad Mórbida/complicaciones , Complicaciones Posoperatorias , Parálisis Respiratoria/cirugía , Anciano , Humanos , Masculino , Reoperación , Parálisis Respiratoria/etiología , Desconexión del Ventilador
9.
Aorta (Stamford) ; 6(1): 37-40, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30079937

RESUMEN

The authors report the case of a patient developing a gluteal compartment syndrome after DeBakey type I dissection repair. Prompt recognition and treatment led to successful results. The surgical approach to the gluteal compartment is described.

11.
Chest ; 144(4): 1207-1215, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23788287

RESUMEN

BACKGROUND: Thrombocytopenia is the most common hemostatic disorder in critically ill patients. The objective of this study was to describe the incidence, risk factors, and outcomes of thrombocytopenia in patients admitted to medical-surgical ICUs. METHODS: Three thousand seven hundred forty-six patients in 67 centers were enrolled in a randomized trial in which unfractionated heparin was compared with low-molecular-weight heparin (LMWH) for thromboprophylaxis. Patients who had baseline platelet counts < 75 × 10(9)/L or severe coagulopathy at screening were excluded. We analyzed the risk of developing mild (100-149 × 10(9)/L), moderate (50-99 × 10(9)/L), and severe (< 50 × 109/L) thrombocytopenia during an ICU stay. We also assessed independent and time-varying predictors of thrombocytopenia and the effect of thrombocytopenia on major bleeding, transfusions, and death. RESULTS: The incidences of mild, moderate, and severe thrombocytopenia were 15.3%, 5.1%, and 1.6%, respectively. The predictors of each category of thrombocytopenia were APACHE (Acute Physiology and Chronic Health Evaluation) II score, use of inotropes or vasopressors, and renal replacement therapy. The risk of moderate thrombocytopenia was lower in patients who received LMWH thromboprophylaxis but higher in surgical patients and in patients who had liver disease. Each category of thrombocytopenia was associated with subsequent bleeding and transfusions. Moderate and severe thrombocytopenia were associated with increased ICU and hospital mortality. CONCLUSION: A high severity of illness, prior surgery, use of inotropes or vasopressors, renal replacement therapy, and liver dysfunction are associated with a higher risk of thrombocytopenia developing in the ICU, whereas LMWH thromboprophylaxis is associated with a lower risk. Patients who develop thrombocytopenia in the ICU are more likely to bleed, receive transfusions, and die.


Asunto(s)
Anticoagulantes/uso terapéutico , Heparina de Bajo-Peso-Molecular/uso terapéutico , Heparina/uso terapéutico , Trombocitopenia/epidemiología , Enfermedad Crítica , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Factores de Riesgo , Método Simple Ciego , Resultado del Tratamiento
12.
Can J Neurol Sci ; 37(4): 492-7, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20724258

RESUMEN

BACKGROUND: In Canada, ancillary tests, such as selective four vessels angiography (S4VA), are sometimes necessary for brain death (BD) diagnosis when the clinical exam cannot be completed or confounding factors are present. Recent Canadian guidelines assert that brain death is supported by the absence of arterial blood flow at the surface of the brain and that venous return should not be considered. However, neuropathologic and angiographic studies have suggested that arteries might still be patent in BD patients. Current clinical practices in BD diagnosis following S4VA need to be better understood. METHODS: We conducted a retrospective study of all S4VA performed for the determination of BD in a level 1 NeuroTrauma centre from 2003 to 2007. The objective of the study was to describe the prevalence of intracranial arterial, capillary (parenchymogram) and venous opacification in our study population. All tests were reviewed independently by two neuroradiologists. Disagreements were resolved by consensus. RESULTS: Thirty two patients were declared BD following S4VA during the study period. Nine of these patients (28%) presented some proximal opacification of intracranial arteries (95% CI 15-45%). As opposed, none had a cerebral capillary and deep venous drainage opacification (95% CI 0-10%). CONCLUSION: The absence of cerebral deep venous drainage or parenchymogram might represent a better objective marker of cerebral circulatory arrest for brain death diagnosis when the use of S4VA is required. These findings open the path for further research in enhancing our interpretation of angiographic studies for brain death diagnosis.


Asunto(s)
Vasos Sanguíneos/patología , Muerte Encefálica/diagnóstico , Angiografía Cerebral/métodos , Adolescente , Adulto , Vasos Sanguíneos/fisiopatología , Circulación Cerebrovascular/fisiología , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Estudios Retrospectivos , Adulto Joven
14.
J Crit Care ; 25(2): 287-93, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20149589

RESUMEN

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is commonly considered but rarely confirmed in critically ill patients. The 4Ts score (Thrombocytopenia, Timing of thrombocytopenia, Thrombosis, and oTher reason) might identify individual patients at risk of having this disorder. OBJECTIVE: The aim of the study was to evaluate the value of the 4Ts HIT score in comparison with the serotonin-release assay (SRA) in critically ill patients. METHODS: This study describes the combined results of 3 prospective studies enrolling critically ill patients who were investigated for HIT if platelets fell to less than 50 x 10(9)/L or if platelet counts decreased to less than 50% of the value upon intensive care unit admission. We confirmed HIT by a positive platelet SRA. We assigned a 4Ts score blinded to SRA results to all 50 patients investigated for HIT; those with positive SRA results were scored in duplicate. RESULTS: Of 528 patients, 50 (9.5%) were investigated for HIT; 39 (78%) of 50 (64%-88%) of these patients were scored as "low probability" by 4Ts score and none had a positive SRA. Of 49 patients who underwent SRA testing because of thrombocytopenia, only 2 (4.1%; 0.5-14.0) had a positive SRA (1 with a moderate 4Ts score and 1 with a high 4Ts score). Therefore, the overall incidence of HIT confirmed by SRA was 2 (0.4%) of 528 (0.04%-1.4%). CONCLUSIONS: Significant thrombocytopenia during heparin administration occurred in 9.5% of critically ill patients, but HIT was confirmed in only 4.1% of those undergoing testing, for an overall incidence of 0.4%. A low 4Ts score occurred in 78% of patients investigated for HIT; none of these patients had a positive SRA. We conclude that HIT is uncommon in critically ill patients and that the 4Ts score is worthy of further evaluation in this patient population.


Asunto(s)
Anticoagulantes/efectos adversos , Ensayo de Inmunoadsorción Enzimática/métodos , Heparina/efectos adversos , Serotonina/metabolismo , Trombocitopenia/diagnóstico , Anciano , Anciano de 80 o más Años , Enfermedad Crítica , Femenino , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Valor Predictivo de las Pruebas , Medición de Riesgo/métodos , Servicio de Cirugía en Hospital , Trombocitopenia/inducido químicamente , Trombocitopenia/metabolismo , Trombosis/diagnóstico
16.
CMAJ ; 175(8): S1, 2006 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-17124739

RESUMEN

These recommendations are the result of a national, multidisciplinary, year-long process to discuss whether and how to proceed with organ donation after cardiocirculatory death (DCD) in Canada. A national forum was held in February 2005 to discuss and develop recommendations on the principles, procedures and practice related to DCD, including ethical and legal considerations. At the forum's conclusion, a strong majority of participants supported proceeding with DCD programs in Canada. The forum also recognized the need to formulate and emphasize core values to guide the development of programs and protocols based on the medical, ethical and legal framework established at this meeting. Although end-of-life care should routinely include the opportunity to donate organs and tissues, the duty of care toward dying patients and their families remains the dominant priority of health care teams. The complexity and profound implications of death are recognized and should be respected, along with differing personal, ethnocultural and religious perspectives on death and donation. Decisions around withdrawal of life-sustaining therapies, management of the dying process and the determination of death by cardiocirculatory criteria should be separate from and independent of donation and transplant processes. The recommendations in this report are intended to guide individual programs, regional health authorities and jurisdictions in the development of DCD protocols. Programs will develop based on local leadership and advance planning that includes education and engagement of stakeholders, mechanisms to assure safety and quality and public information. We recommend that programs begin with controlled DCD within the intensive care unit where (after a consensual decision to withdraw life-sustaining therapy) death is anticipated, but has not yet occurred, and unhurried consent discussions can be held. Uncontrolled donation (where death has occurred after unanticipated cardiac arrest) should only be considered after a controlled DCD program is well established. Although we recommend that programs commence with kidney donation, regional transplant expertise may guide the inclusion of other organs. The impact of DCD, including pre-and post-mortem interventions, on donor family experiences, organ availability, graft function and recipient survival should be carefully documented and studied.


Asunto(s)
Muerte , Cuidado Terminal , Donantes de Tejidos , Obtención de Tejidos y Órganos/ética , Obtención de Tejidos y Órganos/legislación & jurisprudencia , Canadá , Toma de Decisiones , Humanos , Preservación de Órganos , Desarrollo de Programa , Terminología como Asunto , Privación de Tratamiento
17.
Intensive Care Med ; 32(8): 1167-74, 2006 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16794838

RESUMEN

OBJECTIVE: Injury to the alveolocapillary barrier characterizes ALI/ARDS; therefore determining levels of lung epithelium-specific small proteins in serum may help predict clinical outcomes. We examined whether serum Clara cell protein (CC-16) concentration is correlated with the outcome, mechanical ventilation duration, and incidence of nonpulmonary organ failure. DESIGN: Prospective multicenter observational study conducted by the Quebec Critical Care Network. MEASUREMENTS: Seventy-eight adult ARDS patients requiring mechanical ventilation were enrolled and 28-day mortality was the primary outcome. Ventilatory parameters were computed and blood was sampled daily. Clinical information collected included cause of death, duration of mechanical ventilation, number of ventilator-free days, and organ failures. RESULTS: Median serum levels of CC-16 were significantly higher in nonsurvivors than survivors on days 0-2 (19.93 microg/l, IQR 11.8-44.32, vs. 8.9, 5.66-26.38) and sustained up to day 14. CC-16 levels were correlated positively with the number of failing organs (rho 0.3623) and requirement for prolonged mechanical ventilation. Predictors of patient mortality included age, arterial carbon dioxide partial pressure, CC-16, and APACHE II score (odds ratios 1.35, 1.52, 1.37, 1.159, respectively). CONCLUSIONS: Higher initial CC-16 serum level is associated with increased risk of death, fewer ventilator-free days, and increased frequency of nonpulmonary multiple organ failure. CC-16 is a valuable biomarker of ARDS that may help predict outcome among ARDS patients with high-risk mortality.


Asunto(s)
Síndrome de Dificultad Respiratoria/sangre , Uteroglobina/sangre , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Estudios Prospectivos , Respiración Artificial , Síndrome de Dificultad Respiratoria/mortalidad , Síndrome de Dificultad Respiratoria/terapia
18.
Crit Care Med ; 34(8): 2213-6, 2006 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16540953

RESUMEN

OBJECTIVE: To prospectively compare three methods of apnea testing for the confirmation of brain death. DESIGN: Prospective, randomized, crossover study. SETTING: Intensive care unit of a tertiary care university hospital. PATIENTS: Twenty adult patients requiring apnea testing for confirmation of brain death. INTERVENTIONS: Ten minute apnea testing was repeated in random order for every patient with the three oxygenation systems: oxygen catheter inserted through the endotracheal tube (oxygen 6 L/min), T-piece system (oxygen 12 L/min), and continuous positive airway pressure (CPAP) system 10 cm H2O (oxygen 12 L/min). MEASUREMENTS AND MAIN RESULTS: Arterial blood was drawn at 0, 2, 5, and 10 mins of each test. Compared with baseline, Paco2 increased by 30.6 +/- 7.4, 30.0 +/- 7.3 and 30.2 +/- 7.5 mm Hg during the apnea period (p = .96), reaching 73.3 +/- 8.3, 71.6 +/- 11.1, and 72.7 +/- 9.0 mm Hg at the end of the apnea test (p = .73) for the oxygen catheter, the T-piece, and the CPAP, respectively. Pao2 decreased less with the CPAP compared with the oxygen catheter or the T-piece (-22.4 +/- 76, -99.1 +/- 158, and -91.6 +/- 133 mm Hg, respectively, p < .01). In two patients, apnea testing could not be completed with the oxygen catheter and the T-piece because of desaturation, although it could be completed with the CPAP. CONCLUSIONS: The T-piece and the CPAP systems are effective alternatives to the standard oxygen catheter technique for apnea testing. Oxygenation was best maintained with the CPAP system, which can be useful in some patients.


Asunto(s)
Apnea/sangre , Muerte Encefálica/diagnóstico , Presión de las Vías Aéreas Positiva Contínua , Adulto , Anciano , Dióxido de Carbono/sangre , Catéteres de Permanencia , Estudios Cruzados , Femenino , Hospitales Universitarios , Humanos , Unidades de Cuidados Intensivos , Intubación Intratraqueal , Masculino , Persona de Mediana Edad , Oxígeno/sangre , Terapia por Inhalación de Oxígeno/métodos , Estudios Prospectivos
19.
J Crit Care ; 20(4): 364-72, 2005 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16310609

RESUMEN

PURPOSE: There is no randomized trial comparing low-molecular weight heparin (LMWH) and unfractionated heparin (UFH) for thromboprophylaxis in medical-surgical ICU patients. The primary objective of this randomized pilot study on LMWH vs UFH was to assess the feasibility of conducting a large randomized trial with respect to timely enrollment and blinded study drug administration, practicality of twice-weekly lower limb ultrasounds to screen for deep venous thrombosis, LMWH bioaccumulation and dose adjustment in renal insufficiency, and recruitment rates for a future trial in medical-surgical intensive care unit (ICU) patients. Its additional goals were to evaluate the suitability of the exclusion criteria and to document the range of research activities that precede accrual of patients into a trial to plan multisite management. MATERIALS AND METHODS: By computerized telephone randomization, we allocated 129 medical-surgical ICU patients to treatment with dalteparin 5,000 IU QD SC or that with UFH 5,000 IU BID SC. Within each clinical center, only the study pharmacist was not blinded. We performed bilateral lower limb compression ultrasounds within 48 hours of ICU admission, twice weekly, on suspicion of deep venous thrombosis, and 7 days after ICU discharge. Research coordinators and investigators at 7 centers reported the time they engaged in all research activities before the first patient was randomized. RESULTS: Timely complete study drug administration occurred after enrollment. More than 99% of scheduled doses were administered in a blinded fashion. Scheduled ultrasounds were performed without exception. No bioaccumulation of dalteparin was observed when creatinine clearance decreased to lower than 30 mL/min. Average recruitment was 2 patients/center per month before the study exclusion criteria were modified. Study startup activities required, on average, 65.5 hours of combined investigator and research coordinator time at each center. Careful examination of the accrual in the pilot study led to a reexamination of the Prophylaxis of Thromboembolism in Critical Care Trial (PROTECT) study exclusion criteria. CONCLUSIONS: This pilot study suggests that a multicenter randomized clinical trial comparing LMWH with UFH in critically ill medical-surgical patients is feasible. Pilot studies can improve the design of larger trials and may enhance successful timely completion.


Asunto(s)
Anticoagulantes/uso terapéutico , Heparina/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Proyectos de Investigación , Trombosis de la Vena/prevención & control , Australia , Canadá , Método Doble Ciego , Femenino , Heparina de Bajo-Peso-Molecular/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto
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