High- Versus Low-Dose Dexamethasone for the Treatment of COVID-19-Related Acute Respiratory Distress Syndrome: A Multicenter, Randomized Open-Label Clinical Trial.

OBJECTIVE: To determine whether high-dose dexamethasone increases the number of ventilator-free days (VFD) among patients with acute respiratory distress syndrome (ARDS) caused by COVID-19. DESIGN: Multicenter, randomized, open-label, clinical trial. PARTICIPANTS: Consecutive patients with confirmed COVID-19-related ARDS were enrolled from June 17, 2020, to March 27, 2021, in four intensive care units (ICUs) in Argentina. INTERVENTION: 16 mg of dexamethasone intravenously daily for five days followed by 8 mg of dexamethasone daily for five days or 6 mg of dexamethasone intravenously daily for 10 days. MAIN OUTCOME AND MEASURES: The primary outcome was ventilator-free days during the first 28 days. The secondary outcomes were all-cause mortality at 28 and 90 days, infection rate, muscle weakness, and glycemic control in the first 28 days. RESULTS: Data from 98 patients who received at least one dose of dexamethasone were analyzed. The trial was prematurely terminated due to low enrollment rate. At 28 days after randomization, there was no difference between high- and low-dose dexamethasone groups in VFD (median, 0 [interquartile range [IQR] 0-14] vs. 0 [IQR 0-1] days; P = .231), or in the mean duration of mechanical ventilation (19 ± 18 vs. 25 ± 22 days; P = .078). The cumulative hazard of successful discontinuation from mechanical ventilation was increased by the high-dose treatment (adjusted sub-distribution hazard ratio: 1.84; 95% CI: 1.31 to 2.5; P < .001). None of the prespecified secondary and safety outcomes showed a significant difference between treatment arms. CONCLUSIONS: Among patients with ARDS due to COVID-19, the use of higher doses of dexamethasone compared with the recommended low-dose treatment did not show an increase in VFD. However, the higher dose significantly improved the time required to liberate them from the ventilator.

High dose dexamethasone treatment for Acute Respiratory Distress Syndrome secondary to COVID-19: a structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: The aim of this study is to explore the effectiveness and safety of high dose dexamethasone treatment for Acute Respiratory Distress Syndrome secondary to SARS-Cov-2 pneumonia. TRIAL DESIGN: Multicentre, randomized clinical trial, controlled, open label, parallel group, to evaluate the effectiveness and safety of high dose dexamethasone in adult patients with confirmed COVID-19, with Acute Respiratory Distress Syndrome. PARTICIPANTS: We will include patients with SARS-Cov-2 pneumonia who develop acute respiratory distress syndrome, in several intensive care units (ICU) in Buenos Aires, Argentina (CEMIC, Clinica Bazterrica, Sanatorio Sagrado Corazon) Inclusion criteria: Men and women, age ≥ 18 years old. Confirmed diagnosis of SARS-CoV-2 infection, by RT-PCR. Diagnosis of Acute Respiratory Distress Syndrome (hypoxemic respiratory failure not explained by cardiac disease + PaO2/FiO2 ratio < 300 with a Positive End-Expiratory Pressure ≥ 5 cm H2O + bilateral pulmonary infiltrates) Length of mechanical ventilation of at least 72 hours Informed consent (next of kin / legal guardian) Exclusion criteria: Pregnant or breast-feeding women. Terminal disease (advanced cancer; under palliative care; cardiovascular, respiratory, or renal disease with a life expectancy less ≤ 1 year). Therapeutic limitation (advance directives or do not resuscitate order) Severe immunosuppression (HIV infection, long-term use of immunosuppressive agents, active cancer). Patients under chronic treatment with glucocorticoids for other diseases (≥ 8 mg prednisone, or equivalent) Participation in another randomized clinical trial. INTERVENTION AND COMPARATOR: Eligible patients will be randomized to receive standard ICU patient care (group 1) or standard ICU patient care plus high dose dexamethasone (group 2). Group 1: dexamethasone up to 6 mg/24 hours for up to 10 days + ventilatory, hemodynamic, nutritional, and antimicrobial support according to international guidelines. Group 2: dexamethasone 16 mg/24 hours for 5 days followed by dexamethasone 8 mg/24 hours for 5 days + ventilatory, hemodynamic, nutritional, and antimicrobial support according to international guidelines. MAIN OUTCOME: The main result is ventilator-free days at 28 days (Days without ventilator support in the first 28 days following randomization). Secondary outcomes are 28-days and 90-days mortality, frequency of nosocomial infections in the first 28 days after randomization, Sequential Organ Failure Assessment (SOFA) score variation and prone position in the first 10-days, viral shedding 28-days after randomization, and delirium and muscle weakness at ICU discharge. RANDOMISATION: Treatment will be assigned according to site stratified randomization by permuted random blocks sequence 1:1 generated with a table in R language concealed in a randomization tool in REDCap (Research Electronic Data CAPture) platform. BLINDING (MASKING): This is an open trial, so no masking of treatment assignment will be used. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Assuming a 3 days difference in ventilator-free days between treatment groups, with a mean of 9 days, and a standard deviation of 9 days; the necessary sample size would be 284 subjects (142 per group), with a power of 80% and a two-tailed alpha error of 0.05. TRIAL STATUS: The protocol with code 1264, version 3.0 on date: May 13, 2020 is approved by the local Ethics Committee. The trial is in the recruitment phase. Recruitment began May 22, 2020 and is anticipated to be complete by the end of December 2021. TRIAL REGISTRATION: The trial was registered under the title "Dexamethasone for COVID-19 Related ARDS: a Multicenter, Randomized Clinical Trial" with ClinicalTrials number NCT04395105, https://clinicaltrials.gov/ct2/show/NCT04395105 , registered on 20 May 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Gastric tonometry versus cardiac index as resuscitation goals in septic shock: a multicenter, randomized, controlled trial.

INTRODUCTION: Resuscitation goals for septic shock remain controversial. Despite the normalization of systemic hemodynamic variables, tissue hypoperfusion can still persist. Indeed, lactate or oxygen venous saturation may be difficult to interpret. Our hypothesis was that a gastric intramucosal pH-guided resuscitation protocol might improve the outcome of septic shock compared with a standard approach aimed at normalizing systemic parameters such as cardiac index (CI). METHODS: The 130 septic-shock patients were randomized to two different resuscitation goals: CI >or= 3.0 L/min/m2 (CI group: 66 patients) or intramucosal pH (pHi) >or= 7.32 (pHi group: 64 patients). After correcting basic physiologic parameters, additional resuscitation consisting of more fluids and dobutamine was started if specific goals for each group had not been reached. Several clinical data were registered at baseline and during evolution. Hemodynamic data and pHi values were registered every 6 hours during the protocol. Primary end point was 28 days' mortality. RESULTS: Both groups were comparable at baseline. The most frequent sources of infection were abdominal sepsis and pneumonia. Twenty-eight day mortality (30.3 vs. 28.1%), peak Therapeutic Intervention Scoring System scores (32.6 +/- 6.5 vs. 33.2 +/- 4.7) and ICU length of stay (12.6 +/- 8.2 vs. 16 +/- 12.4 days) were comparable. A higher proportion of patients exhibited values below the specific target at baseline in the pHi group compared with the CI group (50% vs. 10.9%; P < 0.001). Of 32 patients with a pHi < 7.32 at baseline, only 7 (22%) normalized this parameter after resuscitation. Areas under the receiver operator characteristic curves to predict mortality at baseline, and at 24 and 48 hours were 0.55, 0.61, and 0.47, and 0.70, 0.90, and 0.75, for CI and pHi, respectively. CONCLUSIONS: Our study failed to demonstrate any survival benefit of using pHi compared with CI as resuscitation goal in septic-shock patients. Nevertheless, a normalization of pHi within 24 hours of resuscitation is a strong signal of therapeutic success, and in contrast, a persistent low pHi despite treatment is associated with a very bad prognosis in septic-shock patients.

[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.

Resolution of ventilator-associated pneumonia: prospective evaluation of the clinical pulmonary infection score as an early clinical predictor of outcome.

OBJECTIVES: To prospectively evaluate the performance of the Clinical Pulmonary Infection Score (CPIS) and its components to identify early in the hospital course of ventilator-associated pneumonia (VAP) which patients are responding to therapy. DESIGN: Prospective, multicenter, in a cohort of mechanically ventilated patients. SETTING: The intensive care unit of six hospitals located in the metropolitan area of Buenos Aires, Argentina. PATIENTS: Sixty-three patients, from a cohort of 472 mechanically ventilated patients hospitalized for >72 hrs, had clinical evidence of VAP and bacteriologic confirmation by bronchoalveolar lavage (BAL) or blood cultures. INTERVENTIONS: Bronchoscopy with BAL fluid culture and blood cultures after establishing a clinical diagnosis of VAP. All patients received antibiotics, 46 before bronchoscopy and 17 immediately after bronchoscopy. MEASUREMENTS AND RESULTS: CPIS was measured at 3 days before VAP (VAP-3); at the onset of VAP (VAP); and at 3 (VAP+3), 5 (VAP+5), and 7 (VAP+7) days after onset. CPIS rose from VAP-3 to VAP and then fell progressively in the population as a whole (p <.001), and the fall in CPIS was significant in 31 survivors, but not in 32 nonsurvivors. From the individual components of the CPIS, only the Pao /Fio ratio distinguished survivors from nonsurvivors, beginning at VAP+3. When CPIS was <6 at 3 or 5 days after VAP onset, mortality was lower than in the remaining patients (p =.018). These differences also related to the finding that those receiving adequate therapy had a slight fall in CPIS and a significant increase of Pao /Fio at VAP+3, whereas those getting inadequate therapy did not. CONCLUSIONS: Serial measurements of CPIS can define the clinical course of VAP resolution, identifying those with good outcome as early as day 3, and could possibly be of help to define strategies to shorten the duration of therapy.

Incidence, clinical course, and outcome in 217 patients with acute respiratory distress syndrome.

OBJECTIVE: To assess prospectively acute respiratory distress syndrome incidence, etiologies, physiologic and clinical features, and mortality and its predictors in four intensive care units in Argentina. DESIGN: Prospective inception cohort. SETTING: Four general intensive care units in teaching hospitals. PATIENTS: All consecutive adult patients admitted between January 3, 1999, and January 6, 2000, that met the criteria of the American-European Consensus Conference for acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 235 patients developed acute respiratory distress syndrome, and 217 survived for >24 hrs; these were further analyzed. Main risk factors were: sepsis (44%, including 65 pneumonia cases), shock (15%), trauma (11%), gastric aspiration (10%), and other (34%). At admission, nonsurvivors had significantly higher Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment and McCabe scores, and lower oxygenation and pH. During the first week, Pao2/Fio2, Sequential Organ Failure Assessment, pH, base excess, and driving pressure consistently discriminated between survivors and nonsurvivors. Hospital mortality was 58%. One third of patients died early. Main causes of death were multiple organ dysfunction syndrome, sepsis, and septic shock; refractory hypoxemia was uncommon. Factors independently associated with mortality were organ dysfunctions on day 3, Pao2/Fio2 on day 3, and McCabe score. CONCLUSIONS: Acute respiratory distress syndrome was a frequent syndrome in this cohort. Sepsis was its leading cause, and pneumonia was the most common single diagnosis. Mortality was high but similar to most recent series that included serious comorbidities. Independent predictors of death 72 hrs after admission emphasize the importance of both extrapulmonary and pulmonary factors together with preexisting severe illnesses.