Telmisartan for treatment of Covid-19 patients: An open multicenter randomized clinical trial.

Background: Angiotensin receptor blockers (ARBs), such as telmisartan, have been postulated to treat Covid-19-induced lung inflammation. Methods: This is a parallel-group, randomized, two-arm, open-label, adaptive, multicenter superiority trial with 1:1 allocation ratio. Participants included patients from 18 years of age hospitalized with Covid-19 with 4 or fewer days since symptom onset enrolled at a university and a community hospital in Buenos Aires, Argentina. Exclusion criteria included prior intensive care unit (ICU) admission and use of ARBs/angiotensin converting enzyme inhibitors at randomization. Control arm received standard care alone and treatment arm telmisartan 80 mg twice daily for 14 days. Primary outcomes were C-reactive protein (CRP) plasma levels at day 5 and 8 after randomization. Secondary outcomes included time to discharge within 15 days, admission to ICU and death at 15- and 30-days. NCT04355936 (Completed). Findings: A pragmatic decision to end the study before the third interim analysis was made on Oct. 30th due to sharp reduction in recruitment. A total of 162 patients were randomized. 158 patients enrolled between May 14 and October 30 2020, were included in the analysis, 80 in the standard care and 78 in the telmisartan added to standard care group. Baseline absolute CRP serum levels were 5.53 ± 6.19 mg/dL (95% CI 6.91 to 4.15, n = 80) and 9.04 ± 7.69 (95% CI 9.04 to 10.82, n = 74) in the standard care and telmisartan added to standard care groups, respectively. Day 5 control-group CRP levels were 6.06 ± 6.95 mg/dL (95% CI 7.79-4.35, n = 66) while telmisartan group were 3.83 ± 5.08 mg/dL (95% CI 5.08-2.59, n = 66, p = 0.038). Day 8 CRP levels were 6.30 ± 8.19 mg/dL (95% CI 8.79-3.81, n = 44) and 2.37 ± 3.47 mg/dL (95% CI 3.44-1.30, n = 43, p = 0.0098) in the control and telmisartan groups, respectively (all values expressed as mean ± SD). Kaplan-Meier analysis showed that telmisartan-treated patients had a lower median time-to-discharge (control=15 days; telmisartan=9 days). Death by day 30 was reduced in the telmisartan-treated group (control 22.54%, 16/71; telmisartan 4.29%, 3/70 participants; p = 0.0023). Composite ICU, mechanical ventilation or death was reduced by telmisartan treatment at days 15 and 30. No adverse events were reported. Interpretation: Our study suggests that the ARB telmisartan, a widely used antihypertensive drug, is safe and could reduce morbidity and mortality in hospitalized patients infected with SARS -CoV-2 by anti-inflammatory effects. Further studies employing telmisartan are needed for confirmation of our results and to define its true therapeutic value as a tool against Covid-19.

Is a strategy based on routine endotracheal cultures the best way to prescribe antibiotics in ventilator-associated pneumonia?

OBJECTIVES: The objectives of this study were to evaluate if a strategy based on routine endotracheal aspirate (ETA) cultures is better than using the American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines to prescribe antimicrobials in ventilator-associated pneumonia (VAP). METHODS: This was a prospective, observational, cohort study conducted in a 15-bed ICU and comprising 283 patients who were mechanically ventilated for ≥48 h. Interventions included twice-weekly ETA; BAL culture was done if VAP was suspected. BAL (collected at the time of VAP) plus ETA cultures (collected≤7 days before VAP) (n=146 different pairs) were defined. We compared two models of 10 days of empirical antimicrobials (ETA-based vs ATS/IDSA guidelines-based strategies), analyzing their impact on appropriateness of therapy and total antimicrobial-days, using the BAL result as the standard for comparison. RESULTS: Complete ETA and BAL culture concordance (identical pathogens or negative result) occurred in 52 pairs; discordance (false positive or false negative) in 67, and partial concordance in two. ETA predicted the etiology in 62.4% of all pairs, in 74.0% of pairs if ETA was performed≤2 days before BAL, and in 46.2% of pairs if ETA was performed 3 to 7 days before BAL (P=.016). Strategies based on the ATS/IDSA guidelines and on ETA results led to appropriate therapy in 97.9% and 77.4% of pairs, respectively (P<.001). The numbers of antimicrobial-days were 1,942 and 1,557 for therapies based on ATS/IDSA guidelines and ETA results, respectively (P<.001). CONCLUSIONS: The ATS/IDSA guidelines-based approach was more accurate than the ETA-based strategy for prescribing appropriate, initial, empirical antibiotics in VAP, unless a sample was available≤2 days of the onset of VAP. The ETA-based strategy led to fewer days on prescribed antimicrobials.

Traqueobronquitis asociada al ventilador (TAV), implicancias del diagnostico clinico y microbiologico en una cohorte de pacientes en ventilacion mecanica / Ventilator associated tracheobronchitis (VAT), implications of clinical and microbiological diagnosis in a cohort of mechanical ventilated patients

Tratar con antibioticos una TAV, proceso intermedio entre colonizacion y neumonia asociada al ventilador (NAV), reduciria la incidencia de NAV y sus consecuencias. Metodos: seguimiento clinico diario y cultivos cuantitativos rutinarios de aspirado traqueal (CRAT) bisemanales hasta el destete en 323 pacientes en ventilacion mecanica. Cuando se sospecho clinicamente infeccion (2/3 criterios), si habia infiltrado radiografico nuevo, se diagnostico NAV y se practico lavado broncoalveolar (LBA) y sin infiltrado nuevo, se diagnostico TAV, se consideraron los aislamientos del LBA positivos (¡Ý 104 unidades formadoras de colonias (ufc)/ml) para la NAV) y del CRAT positivos (¡Ý 103 y < 106 ufc/ml (bajo recuento) y ¡Ý 106 ufc/ml (alto recuento)) para TAV. Resultados: 443 de 2.309 radiografias mostraban ausencia de infiltrado o infiltrado difuso estable; 92 cumplian criterios de TAV, 13 de estas, 12 con CRAT ¡Ý 106 ufc/ml, tuvieron una NAV en los siguientes 3 dias (12 con cultivo de LBA ¡Ý104 ufc/ml). En estas NAV, 11/15 (73.3%) de los pat¨®genos coincidian con los de la TAV precedente. Desde otro punto de vista, 10 TAVs ocurrieron durante la semana posterior a una NAV, solo 4/12(33.3%) patogenos de estas coincidian con los de la TAV, p=0.045 comparando con TAV precediendo a NAV. Setenta TAVs no tuvieron relacion temporal con NAVs. Discusion: este estudio sugiere que tratar con antibioticos las TAVs podria prevenir una NAV en 14% de los casos, exponiendo a un uso innecesario al 86%, lo cual limitaria fuertemente la conveniencia de tratar las TAVs para prevenir las NAVs.

The ventilator associated tracheobronchitis (VAT) is a process between airway colonization and ventilator-associated pneumonia (VAP). The antimicrobial therapy of VAT wouldreduce the incidence of VAP and its consequences. Methods: Daily follow up and twice a week routine quantitative culture of endotracheal aspirates (CETA) up to weaning were performed in 323 mechanically ventilated patients.When a lower respiratory tract infection was suspected (2/3 clinical criteria), if a new radiographic inf¨ªltrate was present, VAP was diagnosed and a bronchoalveolar lavage (BAL) culture was performed; if a radiographic infiltrate was absent, VAT was diagnosed. The bacteriological criteria for diagnosis were a BAL culture positive (¡Ý 104 colony forming units - cfu/ml) for VAP and a CETA positive culture (low count from ¡Ý 103 to < 106 cfu/ml and high count ¡Ý 106 ufc/ml) for VAT. Results: In 443 of 2,309 radiographs an infiltrate was absent or was diffuse and stable; 92 of them met diagnostic clinical criteria for VAT. In 13 (12 with CETA culture ¡Ý 106 cfu/ml), a VAP episode happened during the following 3 days (12 with BAL culture ¡Ý 104 cfu/ml). In 11/15 (73.3%) VAP cases, the isolated pathogens were the same that had been present in the preceding VAT episode. On the other side, ten episodes of VAT were diagnosed during the 7 days after the VAP. Only 4/12 (33.3%) isolated pathogens were the same than those isolated in the VAT preceding the VAP, p=0.045. Seventy VATs had not any temporal relationship with episodes of VAP. Discusion: This study suggests that antimicrobial therapy could prevent a VAP in 14% of the TAV cases. Therefore, exposure to antibiotics was unnecessary in 86% of cases. This finding could represent a severe limitation to the recommendation of treating TAVs with antibiotics to prevent VAPs.

Traqueobronquitis asociada al ventilador (TAV), implicancias del diagnostico clinico y microbiologico en una cohorte de pacientes en ventilacion mecanica / Ventilator associated tracheobronchitis (VAT), implications of clinical and microbiological diagnosis in a cohort of mechanical ventilated patients

Tratar con antibioticos una TAV, proceso intermedio entre colonizacion y neumonia asociada al ventilador (NAV), reduciria la incidencia de NAV y sus consecuencias. Metodos: seguimiento clinico diario y cultivos cuantitativos rutinarios de aspirado traqueal (CRAT) bisemanales hasta el destete en 323 pacientes en ventilacion mecanica. Cuando se sospecho clinicamente infeccion (2/3 criterios), si habia infiltrado radiografico nuevo, se diagnostico NAV y se practico lavado broncoalveolar (LBA) y sin infiltrado nuevo, se diagnostico TAV, se consideraron los aislamientos del LBA positivos (í¦ 104 unidades formadoras de colonias (ufc)/ml) para la NAV) y del CRAT positivos (í¦ 103 y < 106 ufc/ml (bajo recuento) y í¦ 106 ufc/ml (alto recuento)) para TAV. Resultados: 443 de 2.309 radiografias mostraban ausencia de infiltrado o infiltrado difuso estable; 92 cumplian criterios de TAV, 13 de estas, 12 con CRAT í¦ 106 ufc/ml, tuvieron una NAV en los siguientes 3 dias (12 con cultivo de LBA í¦104 ufc/ml). En estas NAV, 11/15 (73.3%) de los pat¿«genos coincidian con los de la TAV precedente. Desde otro punto de vista, 10 TAVs ocurrieron durante la semana posterior a una NAV, solo 4/12(33.3%) patogenos de estas coincidian con los de la TAV, p=0.045 comparando con TAV precediendo a NAV. Setenta TAVs no tuvieron relacion temporal con NAVs. Discusion: este estudio sugiere que tratar con antibioticos las TAVs podria prevenir una NAV en 14% de los casos, exponiendo a un uso innecesario al 86%, lo cual limitaria fuertemente la conveniencia de tratar las TAVs para prevenir las NAVs. (AU)

The ventilator associated tracheobronchitis (VAT) is a process between airway colonization and ventilator-associated pneumonia (VAP). The antimicrobial therapy of VAT wouldreduce the incidence of VAP and its consequences. Methods: Daily follow up and twice a week routine quantitative culture of endotracheal aspirates (CETA) up to weaning were performed in 323 mechanically ventilated patients.When a lower respiratory tract infection was suspected (2/3 clinical criteria), if a new radiographic inf¿¬ltrate was present, VAP was diagnosed and a bronchoalveolar lavage (BAL) culture was performed; if a radiographic infiltrate was absent, VAT was diagnosed. The bacteriological criteria for diagnosis were a BAL culture positive (í¦ 104 colony forming units - cfu/ml) for VAP and a CETA positive culture (low count from í¦ 103 to < 106 cfu/ml and high count í¦ 106 ufc/ml) for VAT. Results: In 443 of 2,309 radiographs an infiltrate was absent or was diffuse and stable; 92 of them met diagnostic clinical criteria for VAT. In 13 (12 with CETA culture í¦ 106 cfu/ml), a VAP episode happened during the following 3 days (12 with BAL culture í¦ 104 cfu/ml). In 11/15 (73.3%) VAP cases, the isolated pathogens were the same that had been present in the preceding VAT episode. On the other side, ten episodes of VAT were diagnosed during the 7 days after the VAP. Only 4/12 (33.3%) isolated pathogens were the same than those isolated in the VAT preceding the VAP, p=0.045. Seventy VATs had not any temporal relationship with episodes of VAP. Discusion: This study suggests that antimicrobial therapy could prevent a VAP in 14% of the TAV cases. Therefore, exposure to antibiotics was unnecessary in 86% of cases. This finding could represent a severe limitation to the recommendation of treating TAVs with antibiotics to prevent VAPs. (AU)

[Acute bilateral emphysematous pyelonephritis. A therapeutic challenge]. / Pielonefritis enfisematosa aguda bilateral un desafio terapeutico.

A therapeutic challenge. Emphysematous pyelonephritis is a rare form of kidney infection characterized by the presence of gas-forming coliform bacteria which affects more frequently diabetic subjects. We report the case of a 57-years-old diabetic woman, who was admitted in septic shock, signs of acute bilateral emphysematous pyelonephritis, and diabetic ketoacidosis. Both blood and urine cultures yielded Escherichia coli. The patient was successfully treated using longterm broad-spectrum antibiotics, diabetic control and supportive measures alone. Catheter drainage and nephrectomy were not necessary to overcome this life threatening situation

Pielonefritis enfisematosa aguda bilateral: un desafío terapéutico / Acute bilateral emphysematous pyelonephritis: a therapeutic challenge

La pielonefritis enfisematosa es una forma poco común de infección renal, caracterizada por la presencia de bacterias coliformes productoras de gas que afecta preferentemente a los pacientes diabéticos. Comunicamos el caso de una mujer diabética de 57 años de edad que ingresó en el hospital por un shock séptico, signos de pielonefritis enfisematosa aguda bilateral y cetoacidosis diabética. En los cultivos de las muestras de orina y sangre desarrolló Escherichia coli. La paciente fue tratada exitosamente con antibióticos de amplio espectro por un tiempo prolongado, control diabético y medidas de sostén solamente. No fue necesario el drenaje con catéteres o la nefrectomía para superar esta situación potencialmente letal.(AU)

Emphysematous pyelonephritis is a rare form of kidney infection characterized by the presence of gas-forming coliform bacteria which affects more frequently diabetic subjects. We report the case of a 57-years-old diabetic woman, who was admitted in septic shock, signs of acute bilateral emphysematous pyelonephritis, and diabetic ketoacidosis. Both blood and urine cultures yielded Escherichia coli. The patient was successfully treated using longterm broad-spectrum antibiotics, diabetic control and supportive measures alone. Catheter drainage and nephrectomy were not necessary to overcome this life threatening situation.(AU)

Pielonefritis enfisematosa aguda bilateral: un desafío terapéutico / Acute bilateral emphysematous pyelonephritis: a therapeutic challenge

La pielonefritis enfisematosa es una forma poco común de infección renal, caracterizada por la presencia de bacterias coliformes productoras de gas que afecta preferentemente a los pacientes diabéticos. Comunicamos el caso de una mujer diabética de 57 años de edad que ingresó en el hospital por un shock séptico, signos de pielonefritis enfisematosa aguda bilateral y cetoacidosis diabética. En los cultivos de las muestras de orina y sangre desarrolló Escherichia coli. La paciente fue tratada exitosamente con antibióticos de amplio espectro por un tiempo prolongado, control diabético y medidas de sostén solamente. No fue necesario el drenaje con catéteres o la nefrectomía para superar esta situación potencialmente letal.

Emphysematous pyelonephritis is a rare form of kidney infection characterized by the presence of gas-forming coliform bacteria which affects more frequently diabetic subjects. We report the case of a 57-years-old diabetic woman, who was admitted in septic shock, signs of acute bilateral emphysematous pyelonephritis, and diabetic ketoacidosis. Both blood and urine cultures yielded Escherichia coli. The patient was successfully treated using longterm broad-spectrum antibiotics, diabetic control and supportive measures alone. Catheter drainage and nephrectomy were not necessary to overcome this life threatening situation.

[Death in an intensive care unit. Influence of life support withholding and withdrawal]. / La muerte en un servicio de terapia intensiva. Influencia de la abstención y retiro del soporte vital.

The influence of life support withholding and withdrawal on the deaths which occurred in an Intensive Care Unit (ICU) over a period of 32 months was analysed. Of 2640 patients admitted in ICU, one of the following five mutually exclusive categories was registered on the 548 patients who died: (i) complete treatment; (ii) complete treatment with non-resuscitation order (NRO); (iii) withholding of life-sustaining treatment; (iv) withdrawal of life-sustaining treatment; and (v) brain death. There was therapeutic limitation of life support in 45.6% of cases (n = 250), with an important majority of withholding (NRO and withholding) in 32.6% of cases, in comparison to withdrawal of life support (8.2% of cases). The comparative analysis with other statistic information suggests the existence of a similar global therapeutic limitation mean in communities with similar cultural background, even if there is a lower influence of life support withdrawal (8.2%) when compared to other countries regardless of their attitude towards the need to establish different degrees of control over technological resources applied to the critically ill. Further research should analyze the influence that moral perception of withdrawal as inconvenient in our society, has over our findings.

La muerte en un servicio de terapia intensiva: influencia de la abstencion y retiro del soporte vital / Death in an intensive care unit: influence of life support withholding and withdrawal

Se estudió la influencia de la abstención y retiro del soporte vital en la muerte ocurrida en un servicio de Terapia Intensiva durante un período de 32 meses. Sobre 2640 pacientes ingresados se registró la conducta terapéutica en 548 muertos, clasificando la misma en cinco categorías: (i) tratamiento completo, (ii) tratamiento completo con orden de no resucitación (ONR), (iii) abstención de soporte vital, (iv) retiro de soporte vital y (v) muerte cerebral. Hubo limitación terapéutica de soporte vital en el 45.6% (n= 250) con unpredominio importante de la abstención (ONR y abstención) en el 32.6% respecto del retiro de soporte vital (8.2%). Del estudio comparativo con otras estadísticas surge el hallazgo de un porcentaje global de limitación terapéutica media cercana a comunidades con una cultura similar, aunque con una incidencia de retiro (8.2%) manifiestamente inferior a la registrada en todos los países cualesquiera fuera su actitud frente a la necesidad de establecer diversos grados de control sobre el recurso tecnológico en el paciente crítico. Deberá indagarse la influencia que tiene la percepción moral del dejar de actuar, como un proceder inconveniente en nuestra sociedad, en los resultados observados.(AU)

The influence of life support withholding and withdrawal on the deaths which occurred in an Intensive Care Unit (ICU) over a period of 32 months was analysed. Of 2640 patients admitted in ICU, one of the following five mutually exclusive categories was registered on the 548 patients who died: (i) complete treatment; (ii) complete treatment with non-resuscitation order (NRO); (iii) withholding of life-sustaining treatment; (iv) withdrawal of life-sustaining treatment; and (v) brain death. There was therapeutic limitation of life support in 45.6% of cases (n=250), with an important majority of withholding (NRO and withholding) in 32.6% of cases, in comparison to withdrawal of life support (8.2% of cases). The comparative analysis with other statistic information suggests the existence of a similar global therapeutic limitation mean in communities with similar cultural background, even if there is a lower influence of life support withdrawal (8.2%) when compared to other countries regardless of their attitude towards the need to establish different degrees of control over technological resources applied to the critically ill. Further research should analyze the influence that moral perception of withdrawal as inconvenient in our society, has over our findings.(AU)

La muerte en un servicio de terapia intensiva: influencia de la abstencion y retiro del soporte vital / Death in an intensive care unit: influence of life support withholding and withdrawal

Se estudió la influencia de la abstención y retiro del soporte vital en la muerte ocurrida en un servicio de Terapia Intensiva durante un período de 32 meses. Sobre 2640 pacientes ingresados se registró la conducta terapéutica en 548 muertos, clasificando la misma en cinco categorías: (i) tratamiento completo, (ii) tratamiento completo con orden de no resucitación (ONR), (iii) abstención de soporte vital, (iv) retiro de soporte vital y (v) muerte cerebral. Hubo limitación terapéutica de soporte vital en el 45.6% (n= 250) con unpredominio importante de la abstención (ONR y abstención) en el 32.6% respecto del retiro de soporte vital (8.2%). Del estudio comparativo con otras estadísticas surge el hallazgo de un porcentaje global de limitación terapéutica media cercana a comunidades con una cultura similar, aunque con una incidencia de retiro (8.2%) manifiestamente inferior a la registrada en todos los países cualesquiera fuera su actitud frente a la necesidad de establecer diversos grados de control sobre el recurso tecnológico en el paciente crítico. Deberá indagarse la influencia que tiene la percepción moral del dejar de actuar, como un proceder inconveniente en nuestra sociedad, en los resultados observados.(AU)

The influence of life support withholding and withdrawal on the deaths which occurred in an Intensive Care Unit (ICU) over a period of 32 months was analysed. Of 2640 patients admitted in ICU, one of the following five mutually exclusive categories was registered on the 548 patients who died: (i) complete treatment; (ii) complete treatment with non-resuscitation order (NRO); (iii) withholding of life-sustaining treatment; (iv) withdrawal of life-sustaining treatment; and (v) brain death. There was therapeutic limitation of life support in 45.6% of cases (n=250), with an important majority of withholding (NRO and withholding) in 32.6% of cases, in comparison to withdrawal of life support (8.2% of cases). The comparative analysis with other statistic information suggests the existence of a similar global therapeutic limitation mean in communities with similar cultural background, even if there is a lower influence of life support withdrawal (8.2%) when compared to other countries regardless of their attitude towards the need to establish different degrees of control over technological resources applied to the critically ill. Further research should analyze the influence that moral perception of withdrawal as inconvenient in our society, has over our findings.(AU)

La muerte en un servicio de terapia intensiva: influencia de la abstencion y retiro del soporte vital / Death in an intensive care unit: influence of life support withholding and withdrawal

Se estudió la influencia de la abstención y retiro del soporte vital en la muerte ocurrida en un servicio de Terapia Intensiva durante un período de 32 meses. Sobre 2640 pacientes ingresados se registró la conducta terapéutica en 548 muertos, clasificando la misma en cinco categorías: (i) tratamiento completo, (ii) tratamiento completo con orden de no resucitación (ONR), (iii) abstención de soporte vital, (iv) retiro de soporte vital y (v) muerte cerebral. Hubo limitación terapéutica de soporte vital en el 45.6% (n= 250) con unpredominio importante de la abstención (ONR y abstención) en el 32.6% respecto del retiro de soporte vital (8.2%). Del estudio comparativo con otras estadísticas surge el hallazgo de un porcentaje global de limitación terapéutica media cercana a comunidades con una cultura similar, aunque con una incidencia de retiro (8.2%) manifiestamente inferior a la registrada en todos los países cualesquiera fuera su actitud frente a la necesidad de establecer diversos grados de control sobre el recurso tecnológico en el paciente crítico. Deberá indagarse la influencia que tiene la percepción moral del dejar de actuar, como un proceder inconveniente en nuestra sociedad, en los resultados observados.

The influence of life support withholding and withdrawal on the deaths which occurred in an Intensive Care Unit (ICU) over a period of 32 months was analysed. Of 2640 patients admitted in ICU, one of the following five mutually exclusive categories was registered on the 548 patients who died: (i) complete treatment; (ii) complete treatment with non-resuscitation order (NRO); (iii) withholding of life-sustaining treatment; (iv) withdrawal of life-sustaining treatment; and (v) brain death. There was therapeutic limitation of life support in 45.6% of cases (n=250), with an important majority of withholding (NRO and withholding) in 32.6% of cases, in comparison to withdrawal of life support (8.2% of cases). The comparative analysis with other statistic information suggests the existence of a similar global therapeutic limitation mean in communities with similar cultural background, even if there is a lower influence of life support withdrawal (8.2%) when compared to other countries regardless of their attitude towards the need to establish different degrees of control over technological resources applied to the critically ill. Further research should analyze the influence that moral perception of withdrawal as inconvenient in our society, has over our findings.