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1.
Am J Respir Crit Care Med ; 205(12): 1419-1428, 2022 Jun 15.
Article in English | MEDLINE | ID: mdl-35349397

ABSTRACT

Rationale: The effects of balanced crystalloid versus saline on clinical outcomes for ICU patients may be modified by the type of fluid that patients received for initial resuscitation and by the type of admission. Objectives: To assess whether the results of a randomized controlled trial could be affected by fluid use before enrollment and admission type. Methods: Secondary post hoc analysis of the BaSICS (Balanced Solution in Intensive Care Study) trial, which compared a balanced solution (Plasma-Lyte 148) with 0.9% saline in the ICU. Patients were categorized according to fluid use in the 24 hours before enrollment in four groups (balanced solutions only, 0.9% saline only, a mix of both, and no fluid before enrollment) and according to admission type (planned, unplanned with sepsis, and unplanned without sepsis). The association between 90-day mortality and the randomization group was assessed using a hierarchical logistic Bayesian model. Measurements and Main Results: A total of 10,520 patients were included. There was a low probability that the balanced solution was associated with improved 90-day mortality in the whole trial population (odds ratio [OR], 0.95; 89% credible interval [CrI], 0.66-10.51; probability of benefit, 0.58); however, probability of benefit was high for patients who received only balanced solutions before enrollment (regardless of admission type, OR, 0.78; 89% CrI, 0.56-1.03; probability of benefit, 0.92), mostly because of a benefit in unplanned admissions due to sepsis (OR, 0.70; 89% CrI, 0.50-0.97; probability of benefit, 0.96) and planned admissions (OR, 0.79; 89% CrI, 0.65-0.97; probability of benefit, 0.97). Conclusions: There is a high probability that balanced solution use in the ICU reduces 90-day mortality in patients who exclusively received balanced fluids before trial enrollment. Clinical trial registered with www.clinicaltrials.gov (NCT02875873).


Subject(s)
Critical Illness , Sepsis , Adult , Bayes Theorem , Critical Illness/therapy , Crystalloid Solutions/therapeutic use , Fluid Therapy/methods , Humans , Saline Solution
2.
Lancet Infect Dis ; 22(3): e74-e87, 2022 03.
Article in English | MEDLINE | ID: mdl-34774188

ABSTRACT

During the current COVID-19 pandemic, health-care workers and uninfected patients in intensive care units (ICUs) are at risk of being infected with SARS-CoV-2 as a result of transmission from infected patients and health-care workers. In the absence of high-quality evidence on the transmission of SARS-CoV-2, clinical practice of infection control and prevention in ICUs varies widely. Using a Delphi process, international experts in intensive care, infectious diseases, and infection control developed consensus statements on infection control for SARS-CoV-2 in an ICU. Consensus was achieved for 31 (94%) of 33 statements, from which 25 clinical practice statements were issued. These statements include guidance on ICU design and engineering, health-care worker safety, visiting policy, personal protective equipment, patients and procedures, disinfection, and sterilisation. Consensus was not reached on optimal return to work criteria for health-care workers who were infected with SARS-CoV-2 or the acceptable disinfection strategy for heat-sensitive instruments used for airway management of patients with SARS-CoV-2 infection. Well designed studies are needed to assess the effects of these practice statements and address the remaining uncertainties.


Subject(s)
COVID-19 , Consensus , Infection Control/standards , Infectious Disease Transmission, Patient-to-Professional/prevention & control , Intensive Care Units/standards , SARS-CoV-2/isolation & purification , COVID-19 Vaccines/administration & dosage , Delphi Technique , Health Personnel/standards , Humans , Personal Protective Equipment/standards
3.
Crit Care Med ; 49(11): 1974-1982, 2021 11 01.
Article in English | MEDLINE | ID: mdl-34643578
4.
Crit Care Med ; 49(11): e1063-e1143, 2021 11 01.
Article in English | MEDLINE | ID: mdl-34605781
6.
JAMA ; 326(9): 830-838, 2021 09 07.
Article in English | MEDLINE | ID: mdl-34547081

ABSTRACT

Importance: Slower intravenous fluid infusion rates could reduce the formation of tissue edema and organ dysfunction in critically ill patients; however, there are no data to support different infusion rates during fluid challenges for important outcomes such as mortality. Objective: To determine the effect of a slower infusion rate vs control infusion rate on 90-day survival in patients in the intensive care unit (ICU). Design, Setting, and Participants: Unblinded randomized factorial clinical trial in 75 ICUs in Brazil, involving 11 052 patients requiring at least 1 fluid challenge and with 1 risk factor for worse outcomes were randomized from May 29, 2017, to March 2, 2020. Follow-up was concluded on October 29, 2020. Patients were randomized to 2 different infusion rates (reported in this article) and 2 different fluid types (balanced fluids or saline, reported separately). Interventions: Patients were randomized to receive fluid challenges at 2 different infusion rates; 5538 to the slower rate (333 mL/h) and 5514 to the control group (999 mL/h). Patients were also randomized to receive balanced solution or 0.9% saline using a factorial design. Main Outcomes and Measures: The primary end point was 90-day survival. Results: Of all randomized patients, 10 520 (95.2%) were analyzed (mean age, 61.1 years [SD, 17.0 years]; 44.2% were women) after excluding duplicates and consent withdrawals. Patients assigned to the slower rate received a mean of 1162 mL on the first day vs 1252 mL for the control group. By day 90, 1406 of 5276 patients (26.6%) in the slower rate group had died vs 1414 of 5244 (27.0%) in the control group (adjusted hazard ratio, 1.03; 95% CI, 0.96-1.11; P = .46). There was no significant interaction between fluid type and infusion rate (P = .98). Conclusions and Relevance: Among patients in the intensive care unit requiring fluid challenges, infusing at a slower rate compared with a faster rate did not reduce 90-day mortality. These findings do not support the use of a slower infusion rate. Trial Registration: ClinicalTrials.gov Identifier: NCT02875873.


Subject(s)
Critical Illness/mortality , Critical Illness/therapy , Fluid Therapy/methods , Adult , Aged , Female , Hospital Mortality , Humans , Infusions, Intravenous , Intensive Care Units , Male , Middle Aged , Proportional Hazards Models
8.
JAMA ; 2021 Aug 10.
Article in English | MEDLINE | ID: mdl-34375394

ABSTRACT

IMPORTANCE: Intravenous fluids are used for almost all intensive care unit (ICU) patients. Clinical and laboratory studies have questioned whether specific fluid types result in improved outcomes, including mortality and acute kidney injury. OBJECTIVE: To determine the effect of a balanced solution vs saline solution (0.9% sodium chloride) on 90-day survival in critically ill patients. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, factorial, randomized clinical trial conducted at 75 ICUs in Brazil. Patients who were admitted to the ICU with at least 1 risk factor for worse outcomes, who required at least 1 fluid expansion, and who were expected to remain in the ICU for more than 24 hours were randomized between May 29, 2017, and March 2, 2020; follow-up concluded on October 29, 2020. Patients were randomized to 2 different fluid types (a balanced solution vs saline solution reported in this article) and 2 different infusion rates (reported separately). INTERVENTIONS: Patients were randomly assigned 1:1 to receive either a balanced solution (n = 5522) or 0.9% saline solution (n = 5530) for all intravenous fluids. MAIN OUTCOMES AND MEASURES: The primary outcome was 90-day survival. RESULTS: Among 11 052 patients who were randomized, 10 520 (95.2%) were available for the analysis (mean age, 61.1 [SD, 17] years; 44.2% were women). There was no significant interaction between the 2 interventions (fluid type and infusion speed; P = .98). Planned surgical admissions represented 48.4% of all patients. Of all the patients, 60.6% had hypotension or vasopressor use and 44.3% required mechanical ventilation at enrollment. Patients in both groups received a median of 1.5 L of fluid during the first day after enrollment. By day 90, 1381 of 5230 patients (26.4%) assigned to a balanced solution died vs 1439 of 5290 patients (27.2%) assigned to saline solution (adjusted hazard ratio, 0.97 [95% CI, 0.90-1.05]; P = .47). There were no unexpected treatment-related severe adverse events in either group. CONCLUSION AND RELEVANCE: Among critically ill patients requiring fluid challenges, use of a balanced solution compared with 0.9% saline solution did not significantly reduce 90-day mortality. The findings do not support the use of this balanced solution. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02875873.

9.
Intensive Care Med Exp ; 9(1): 34, 2021 Jul 02.
Article in English | MEDLINE | ID: mdl-34212256

ABSTRACT

OBJECTIVE: To identify priorities for administrative, epidemiologic and diagnostic research in sepsis. DESIGN: As a follow-up to a previous consensus statement about sepsis research, members of the Surviving Sepsis Campaign Research Committee, representing the European Society of Intensive Care Medicine and the Society of Critical Care Medicine addressed six questions regarding care delivery, epidemiology, organ dysfunction, screening, identification of septic shock, and information that can predict outcomes in sepsis. METHODS: Six questions from the Scoring/Identification and Administration sections of the original Research Priorities publication were explored in greater detail to better examine the knowledge gaps and rationales for questions that were previously identified through a consensus process. RESULTS: The document provides a framework for priorities in research to address the following questions: (1) What is the optimal model of delivering sepsis care?; (2) What is the epidemiology of sepsis susceptibility and response to treatment?; (3) What information identifies organ dysfunction?; (4) How can we screen for sepsis in various settings?; (5) How do we identify septic shock?; and (6) What in-hospital clinical information is associated with important outcomes in patients with sepsis? CONCLUSIONS: There is substantial knowledge of sepsis epidemiology and ways to identify and treat sepsis patients, but many gaps remain. Areas of uncertainty identified in this manuscript can help prioritize initiatives to improve an understanding of individual patient and demographic heterogeneity with sepsis and septic shock, biomarkers and accurate patient identification, organ dysfunction, and ways to improve sepsis care.

10.
Am Heart J ; 238: 1-11, 2021 08.
Article in English | MEDLINE | ID: mdl-33891907

ABSTRACT

BACKGROUND: Observational studies have suggested a higher risk of thrombotic events in patients with coronavirus disease 2019 (COVID-19). Moreover, elevated D-dimer levels have been identified as an important prognostic marker in COVID-19 directly associated with disease severity and progression. Prophylactic anticoagulation for hospitalized COVID-19 patients might not be enough to prevent thrombotic events; therefore, therapeutic anticoagulation regimens deserve clinical investigation. DESIGN: ACTION is an academic-led, pragmatic, multicenter, open-label, randomized, phase IV clinical trial that aims to enroll around 600 patients at 40 sites participating in the Coalition COVID-19 Brazil initiative. Eligible patients with a confirmed diagnosis of COVID-19 with symptoms up to 14 days and elevated D-dimer levels will be randomized to a strategy of full-dose anticoagulation for 30 days with rivaroxaban 20 mg once daily (or full-dose heparin if oral administration is not feasible) vs standard of care with any approved venous thromboembolism prophylaxis regimen during hospitalization. A confirmation of COVID-19 was mandatory for study entry, based on specific tests used in clinical practice (RT-PCR, antigen test, IgM test) collected before randomization, regardless of in the outpatient setting or not. Randomization will be stratified by clinical stability at presentation. The primary outcome is a hierarchical analysis of mortality, length of hospital stay, or duration of oxygen therapy at the end of 30 days. Secondary outcomes include the World Health Organization's 8-point ordinal scale at 30 days and the following efficacy outcomes: incidence of venous thromboembolism , acute myocardial infarction, stroke, systemic embolism, major adverse limb events, duration of oxygen therapy, disease progression, and biomarkers. The primary safety outcomes are major or clinically relevant non-major bleeding according to the International Society on Thrombosis and Haemostasis criteria. SUMMARY: The ACTION trial will evaluate whether in-hospital therapeutic anticoagulation with rivaroxaban for stable patients, or enoxaparin for unstable patients, followed by rivaroxaban through 30 days compared with standard prophylactic anticoagulation improves clinical outcomes in hospitalized patients with COVID-19 and elevated D-dimer levels.


Subject(s)
Anticoagulants/therapeutic use , COVID-19/complications , Enoxaparin/therapeutic use , Rivaroxaban/therapeutic use , Thrombosis/prevention & control , Administration, Oral , Anticoagulants/administration & dosage , Anticoagulants/adverse effects , Brazil , COVID-19/blood , COVID-19/mortality , Drug Administration Schedule , Enoxaparin/administration & dosage , Enoxaparin/adverse effects , Fibrin Fibrinogen Degradation Products/analysis , Hemorrhage/chemically induced , Hospitalization , Humans , Oxygen Inhalation Therapy , Rivaroxaban/administration & dosage , Rivaroxaban/adverse effects , Thrombosis/etiology , Time Factors
11.
Crit Care ; 25(1): 106, 2021 03 16.
Article in English | MEDLINE | ID: mdl-33726819

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) pandemic has caused unprecedented pressure on healthcare system globally. Lack of high-quality evidence on the respiratory management of COVID-19-related acute respiratory failure (C-ARF) has resulted in wide variation in clinical practice. METHODS: Using a Delphi process, an international panel of 39 experts developed clinical practice statements on the respiratory management of C-ARF in areas where evidence is absent or limited. Agreement was defined as achieved when > 70% experts voted for a given option on the Likert scale statement or > 80% voted for a particular option in multiple-choice questions. Stability was assessed between the two concluding rounds for each statement, using the non-parametric Chi-square (χ2) test (p < 0·05 was considered as unstable). RESULTS: Agreement was achieved for 27 (73%) management strategies which were then used to develop expert clinical practice statements. Experts agreed that COVID-19-related acute respiratory distress syndrome (ARDS) is clinically similar to other forms of ARDS. The Delphi process yielded strong suggestions for use of systemic corticosteroids for critical COVID-19; awake self-proning to improve oxygenation and high flow nasal oxygen to potentially reduce tracheal intubation; non-invasive ventilation for patients with mixed hypoxemic-hypercapnic respiratory failure; tracheal intubation for poor mentation, hemodynamic instability or severe hypoxemia; closed suction systems; lung protective ventilation; prone ventilation (for 16-24 h per day) to improve oxygenation; neuromuscular blocking agents for patient-ventilator dyssynchrony; avoiding delay in extubation for the risk of reintubation; and similar timing of tracheostomy as in non-COVID-19 patients. There was no agreement on positive end expiratory pressure titration or the choice of personal protective equipment. CONCLUSION: Using a Delphi method, an agreement among experts was reached for 27 statements from which 20 expert clinical practice statements were derived on the respiratory management of C-ARF, addressing important decisions for patient management in areas where evidence is either absent or limited. TRIAL REGISTRATION: The study was registered with Clinical trials.gov Identifier: NCT04534569.


Subject(s)
COVID-19/complications , Consensus , Delphi Technique , Respiratory Insufficiency/therapy , Respiratory Insufficiency/virology , Humans
12.
Intensive Care Med ; 47(3): 282-291, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33616696

ABSTRACT

Coronavirus disease 19 (COVID-19) has posed unprecedented healthcare system challenges, some of which will lead to transformative change. It is obvious to healthcare workers and policymakers alike that an effective critical care surge response must be nested within the overall care delivery model. The COVID-19 pandemic has highlighted key elements of emergency preparedness. These include having national or regional strategic reserves of personal protective equipment, intensive care unit (ICU) devices, consumables and pharmaceuticals, as well as effective supply chains and efficient utilization protocols. ICUs must also be prepared to accommodate surges of patients and ICU staffing models should allow for fluctuations in demand. Pre-existing ICU triage and end-of-life care principles should be established, implemented and updated. Daily workflow processes should be restructured to include remote connection with multidisciplinary healthcare workers and frequent communication with relatives. The pandemic has also demonstrated the benefits of digital transformation and the value of remote monitoring technologies, such as wireless monitoring. Finally, the pandemic has highlighted the value of pre-existing epidemiological registries and agile randomized controlled platform trials in generating fast, reliable data. The COVID-19 pandemic is a reminder that besides our duty to care, we are committed to improve. By meeting these challenges today, we will be able to provide better care to future patients.


Subject(s)
COVID-19 , Critical Care/trends , Pandemics , Critical Care/organization & administration , Disaster Planning , Humans , Intensive Care Units/organization & administration , Monitoring, Physiologic/instrumentation , Monitoring, Physiologic/methods , Personal Protective Equipment , Surge Capacity , Telemedicine , Workflow
13.
BMJ ; 372: n84, 2021 01 20.
Article in English | MEDLINE | ID: mdl-33472855

ABSTRACT

OBJECTIVE: To determine whether tocilizumab improves clinical outcomes for patients with severe or critical coronavirus disease 2019 (covid-19). DESIGN: Randomised, open label trial. SETTING: Nine hospitals in Brazil, 8 May to 17 July 2020. PARTICIPANTS: Adults with confirmed covid-19 who were receiving supplemental oxygen or mechanical ventilation and had abnormal levels of at least two serum biomarkers (C reactive protein, D dimer, lactate dehydrogenase, or ferritin). The data monitoring committee recommended stopping the trial early, after 129 patients had been enrolled, because of an increased number of deaths at 15 days in the tocilizumab group. INTERVENTIONS: Tocilizumab (single intravenous infusion of 8 mg/kg) plus standard care (n=65) versus standard care alone (n=64). MAIN OUTCOME MEASURE: The primary outcome, clinical status measured at 15 days using a seven level ordinal scale, was analysed as a composite of death or mechanical ventilation because the assumption of odds proportionality was not met. RESULTS: A total of 129 patients were enrolled (mean age 57 (SD 14) years; 68% men) and all completed follow-up. All patients in the tocilizumab group and two in the standard care group received tocilizumab. 18 of 65 (28%) patients in the tocilizumab group and 13 of 64 (20%) in the standard care group were receiving mechanical ventilation or died at day 15 (odds ratio 1.54, 95% confidence interval 0.66 to 3.66; P=0.32). Death at 15 days occurred in 11 (17%) patients in the tocilizumab group compared with 2 (3%) in the standard care group (odds ratio 6.42, 95% confidence interval 1.59 to 43.2). Adverse events were reported in 29 of 67 (43%) patients who received tocilizumab and 21 of 62 (34%) who did not receive tocilizumab. CONCLUSIONS: In patients with severe or critical covid-19, tocilizumab plus standard care was not superior to standard care alone in improving clinical outcomes at 15 days, and it might increase mortality. TRIAL REGISTRATION: ClinicalTrials.gov NCT04403685.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/mortality , COVID-19/therapy , Critical Illness , Female , Follow-Up Studies , Hospitalization , Humans , Infusions, Intravenous , Male , Middle Aged , Respiration, Artificial , Severity of Illness Index , Treatment Outcome , Young Adult
14.
BMJ ; 370: [1-14], Sept. 04, 2020.
Article in English | BIGG, BIGG | ID: biblio-1129878

ABSTRACT

What is the role of drug interventions in the treatment of patients with covid-19? The latest version of this WHO living guidance focuses on remdesivir, following the 15 October 2020 preprint publication of results from the WHO SOLIDARITY trial. It contains a weak or conditional recommendation against the use of remdesivir in hospitalised patients with covid-19 The first version on this living guidance focused on corticosteroids. The strong recommendation for systemic corticosteroids in patients with severe and critical covid-19, and a weak or conditional recommendation against systemic corticosteroids in patients with non-severe covid-19 are unchanged.


Subject(s)
Humans , Adrenal Cortex Hormones/therapeutic use , Anti-Retroviral Agents/therapeutic use , COVID-19/drug therapy , Severity of Illness Index , Ivermectin/therapeutic use , Lopinavir/therapeutic use , Hydroxychloroquine/therapeutic use , Immunologic Factors/therapeutic use
15.
Lancet ; 396(10256): 959-967, 2020 10 03.
Article in English | MEDLINE | ID: mdl-32896292

ABSTRACT

BACKGROUND: The efficacy and safety of azithromycin in the treatment of COVID-19 remain uncertain. We assessed whether adding azithromycin to standard of care, which included hydroxychloroquine, would improve clinical outcomes of patients admitted to the hospital with severe COVID-19. METHODS: We did an open-label, randomised clinical trial at 57 centres in Brazil. We enrolled patients admitted to hospital with suspected or confirmed COVID-19 and at least one additional severity criteria as follows: use of oxygen supplementation of more than 4 L/min flow; use of high-flow nasal cannula; use of non-invasive mechanical ventilation; or use of invasive mechanical ventilation. Patients were randomly assigned (1:1) to azithromycin (500 mg via oral, nasogastric, or intravenous administration once daily for 10 days) plus standard of care or to standard of care without macrolides. All patients received hydroxychloroquine (400 mg twice daily for 10 days) because that was part of standard of care treatment in Brazil for patients with severe COVID-19. The primary outcome, assessed by an independent adjudication committee masked to treatment allocation, was clinical status at day 15 after randomisation, assessed by a six-point ordinal scale, with levels ranging from 1 to 6 and higher scores indicating a worse condition (with odds ratio [OR] greater than 1·00 favouring the control group). The primary outcome was assessed in all patients in the intention-to-treat (ITT) population who had severe acute respiratory syndrome coronavirus 2 infection confirmed by molecular or serological testing before randomisation (ie, modified ITT [mITT] population). Safety was assessed in all patients according to which treatment they received, regardless of original group assignment. This trial was registered at ClinicalTrials.gov, NCT04321278. FINDINGS: 447 patients were enrolled from March 28 to May 19, 2020. COVID-19 was confirmed in 397 patients who constituted the mITT population, of whom 214 were assigned to the azithromycin group and 183 to the control group. In the mITT population, the primary endpoint was not significantly different between the azithromycin and control groups (OR 1·36 [95% CI 0·94-1·97], p=0·11). Rates of adverse events, including clinically relevant ventricular arrhythmias, resuscitated cardiac arrest, acute kidney failure, and corrected QT interval prolongation, were not significantly different between groups. INTERPRETATION: In patients with severe COVID-19, adding azithromycin to standard of care treatment (which included hydroxychloroquine) did not improve clinical outcomes. Our findings do not support the routine use of azithromycin in combination with hydroxychloroquine in patients with severe COVID-19. FUNDING: COALITION COVID-19 Brazil and EMS.


Subject(s)
Antiviral Agents/therapeutic use , Azithromycin/therapeutic use , Coronavirus Infections/drug therapy , Hydroxychloroquine/therapeutic use , Pneumonia, Viral/drug therapy , Aged , Antiviral Agents/adverse effects , Azithromycin/adverse effects , Betacoronavirus , Brazil/epidemiology , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/mortality , Drug Therapy, Combination , Female , Humans , Hydroxychloroquine/adverse effects , Length of Stay , Male , Middle Aged , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/mortality , Respiratory Therapy , SARS-CoV-2 , Standard of Care , Treatment Outcome
16.
JAMA ; 324(13): 1330-1341, 2020 10 06.
Article in English | MEDLINE | ID: mdl-32876694

ABSTRACT

Importance: Effective therapies for patients with coronavirus disease 2019 (COVID-19) are needed, and clinical trial data have demonstrated that low-dose dexamethasone reduced mortality in hospitalized patients with COVID-19 who required respiratory support. Objective: To estimate the association between administration of corticosteroids compared with usual care or placebo and 28-day all-cause mortality. Design, Setting, and Participants: Prospective meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19. The trials were conducted in 12 countries from February 26, 2020, to June 9, 2020, and the date of final follow-up was July 6, 2020. Pooled data were aggregated from the individual trials, overall, and in predefined subgroups. Risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effect meta-analysis of overall mortality, with the association between the intervention and mortality quantified using odds ratios (ORs). Random-effects meta-analyses also were conducted (with the Paule-Mandel estimate of heterogeneity and the Hartung-Knapp adjustment) and an inverse variance-weighted fixed-effect analysis using risk ratios. Exposures: Patients had been randomized to receive systemic dexamethasone, hydrocortisone, or methylprednisolone (678 patients) or to receive usual care or placebo (1025 patients). Main Outcomes and Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. A secondary outcome was investigator-defined serious adverse events. Results: A total of 1703 patients (median age, 60 years [interquartile range, 52-68 years]; 488 [29%] women) were included in the analysis. Risk of bias was assessed as "low" for 6 of the 7 mortality results and as "some concerns" in 1 trial because of the randomization method. Five trials reported mortality at 28 days, 1 trial at 21 days, and 1 trial at 30 days. There were 222 deaths among the 678 patients randomized to corticosteroids and 425 deaths among the 1025 patients randomized to usual care or placebo (summary OR, 0.66 [95% CI, 0.53-0.82]; P < .001 based on a fixed-effect meta-analysis). There was little inconsistency between the trial results (I2 = 15.6%; P = .31 for heterogeneity) and the summary OR was 0.70 (95% CI, 0.48-1.01; P = .053) based on the random-effects meta-analysis. The fixed-effect summary OR for the association with mortality was 0.64 (95% CI, 0.50-0.82; P < .001) for dexamethasone compared with usual care or placebo (3 trials, 1282 patients, and 527 deaths), the OR was 0.69 (95% CI, 0.43-1.12; P = .13) for hydrocortisone (3 trials, 374 patients, and 94 deaths), and the OR was 0.91 (95% CI, 0.29-2.87; P = .87) for methylprednisolone (1 trial, 47 patients, and 26 deaths). Among the 6 trials that reported serious adverse events, 64 events occurred among 354 patients randomized to corticosteroids and 80 events occurred among 342 patients randomized to usual care or placebo. Conclusions and Relevance: In this prospective meta-analysis of clinical trials of critically ill patients with COVID-19, administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , Coronavirus Infections/drug therapy , Glucocorticoids/therapeutic use , Pneumonia, Viral/drug therapy , Betacoronavirus , COVID-19 , Cause of Death , Coronavirus Infections/mortality , Critical Illness , Dexamethasone/therapeutic use , Humans , Hydrocortisone/therapeutic use , Methylprednisolone/therapeutic use , Pandemics , Pneumonia, Viral/mortality , Randomized Controlled Trials as Topic , SARS-CoV-2
17.
JAMA ; 324(13): 1307-1316, 2020 10 06.
Article in English | MEDLINE | ID: mdl-32876695

ABSTRACT

Importance: Acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) is associated with substantial mortality and use of health care resources. Dexamethasone use might attenuate lung injury in these patients. Objective: To determine whether intravenous dexamethasone increases the number of ventilator-free days among patients with COVID-19-associated ARDS. Design, Setting, and Participants: Multicenter, randomized, open-label, clinical trial conducted in 41 intensive care units (ICUs) in Brazil. Patients with COVID-19 and moderate to severe ARDS, according to the Berlin definition, were enrolled from April 17 to June 23, 2020. Final follow-up was completed on July 21, 2020. The trial was stopped early following publication of a related study before reaching the planned sample size of 350 patients. Interventions: Twenty mg of dexamethasone intravenously daily for 5 days, 10 mg of dexamethasone daily for 5 days or until ICU discharge, plus standard care (n =151) or standard care alone (n = 148). Main Outcomes and Measures: The primary outcome was ventilator-free days during the first 28 days, defined as being alive and free from mechanical ventilation. Secondary outcomes were all-cause mortality at 28 days, clinical status of patients at day 15 using a 6-point ordinal scale (ranging from 1, not hospitalized to 6, death), ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, and Sequential Organ Failure Assessment (SOFA) scores (range, 0-24, with higher scores indicating greater organ dysfunction) at 48 hours, 72 hours, and 7 days. Results: A total of 299 patients (mean [SD] age, 61 [14] years; 37% women) were enrolled and all completed follow-up. Patients randomized to the dexamethasone group had a mean 6.6 ventilator-free days (95% CI, 5.0-8.2) during the first 28 days vs 4.0 ventilator-free days (95% CI, 2.9-5.4) in the standard care group (difference, 2.26; 95% CI, 0.2-4.38; P = .04). At 7 days, patients in the dexamethasone group had a mean SOFA score of 6.1 (95% CI, 5.5-6.7) vs 7.5 (95% CI, 6.9-8.1) in the standard care group (difference, -1.16; 95% CI, -1.94 to -0.38; P = .004). There was no significant difference in the prespecified secondary outcomes of all-cause mortality at 28 days, ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, or the 6-point ordinal scale at 15 days. Thirty-three patients (21.9%) in the dexamethasone group vs 43 (29.1%) in the standard care group experienced secondary infections, 47 (31.1%) vs 42 (28.3%) needed insulin for glucose control, and 5 (3.3%) vs 9 (6.1%) experienced other serious adverse events. Conclusions and Relevance: Among patients with COVID-19 and moderate or severe ARDS, use of intravenous dexamethasone plus standard care compared with standard care alone resulted in a statistically significant increase in the number of ventilator-free days (days alive and free of mechanical ventilation) over 28 days. Trial Registration: ClinicalTrials.gov Identifier: NCT04327401.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Coronavirus Infections/drug therapy , Dexamethasone/therapeutic use , Pneumonia, Viral/drug therapy , Respiration, Artificial/statistics & numerical data , Respiratory Distress Syndrome/drug therapy , Administration, Intravenous , Aged , Anti-Inflammatory Agents/adverse effects , Betacoronavirus , Brazil , COVID-19 , Catheter-Related Infections/epidemiology , Coronavirus Infections/complications , Coronavirus Infections/mortality , Coronavirus Infections/therapy , Dexamethasone/adverse effects , Early Termination of Clinical Trials , Female , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/mortality , Pneumonia, Viral/therapy , Respiratory Distress Syndrome/etiology , SARS-CoV-2
18.
Aust Crit Care ; 34(1): 23-32, 2021 01.
Article in English | MEDLINE | ID: mdl-32828672

ABSTRACT

OBJECTIVE: Fluid resuscitation is a ubiquitous intervention in the management of patients treated in the intensive care unit, which has implications for intensive care unit resourcing and budgets. Our objective was to calculate the relative cost of resuscitation fluids in several countries to inform future economic evaluations. METHODS: We collected site-level data regarding the availability and cost of fluids as part of an international survey. We normalised costs to net present values using purchasing power parities and published inflation figures. Costs were also adjusted for equi-effective dosing based on intravascular volume expansion effectiveness and expressed as US dollars (USD) per 100 mL crystalloid equivalent. RESULTS: A total of 187 sites had access to cost data. Between countries, there was an approximate six fold variation in the cost of crystalloids and colloids overall. The average cost for crystalloids overall was less than 1 USD per 100 mL. In contrast, colloid fluids had higher average costs (59 USD per 100 mL). After adjusting for equi-effective dosing, saline was ∼27 times less costly than albumin (saline: 0.6 USD per 100 mL crystalloid equivalent; albumin 4-5%: 16.4 USD; albumin 20-25%: 15.8 USD) and ∼4 times less costly than hydroxyethyl starch solution (saline: 0.6 USD; hydroxyethyl starch solution: 2.5 USD). Buffered salt solutions, such as compound sodium acetate solutions (e.g., Plasmalyte®), had the highest average cost of crystalloid fluids, costing between 3 and 4 USD per 100 mL. CONCLUSION: The cost of fluid varies substantially between fluid types and between countries, although normal (0.9%) saline is consistently less costly than colloid preparations and some buffered salt solutions. These data can be used to inform future economic evaluations of fluid preparations.


Subject(s)
Fluid Therapy/economics , Plasma Substitutes , Rehydration Solutions , Crystalloid Solutions/economics , Health Care Costs , Humans , Internationality , Isotonic Solutions/economics , Plasma Substitutes/economics , Plasma Substitutes/therapeutic use , Rehydration Solutions/economics , Resuscitation
19.
N Engl J Med ; 383(21): 2041-2052, 2020 11 19.
Article in English | MEDLINE | ID: mdl-32706953

ABSTRACT

BACKGROUND: Hydroxychloroquine and azithromycin have been used to treat patients with coronavirus disease 2019 (Covid-19). However, evidence on the safety and efficacy of these therapies is limited. METHODS: We conducted a multicenter, randomized, open-label, three-group, controlled trial involving hospitalized patients with suspected or confirmed Covid-19 who were receiving either no supplemental oxygen or a maximum of 4 liters per minute of supplemental oxygen. Patients were randomly assigned in a 1:1:1 ratio to receive standard care, standard care plus hydroxychloroquine at a dose of 400 mg twice daily, or standard care plus hydroxychloroquine at a dose of 400 mg twice daily plus azithromycin at a dose of 500 mg once daily for 7 days. The primary outcome was clinical status at 15 days as assessed with the use of a seven-level ordinal scale (with levels ranging from one to seven and higher scores indicating a worse condition) in the modified intention-to-treat population (patients with a confirmed diagnosis of Covid-19). Safety was also assessed. RESULTS: A total of 667 patients underwent randomization; 504 patients had confirmed Covid-19 and were included in the modified intention-to-treat analysis. As compared with standard care, the proportional odds of having a higher score on the seven-point ordinal scale at 15 days was not affected by either hydroxychloroquine alone (odds ratio, 1.21; 95% confidence interval [CI], 0.69 to 2.11; P = 1.00) or hydroxychloroquine plus azithromycin (odds ratio, 0.99; 95% CI, 0.57 to 1.73; P = 1.00). Prolongation of the corrected QT interval and elevation of liver-enzyme levels were more frequent in patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent. CONCLUSIONS: Among patients hospitalized with mild-to-moderate Covid-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as compared with standard care. (Funded by the Coalition Covid-19 Brazil and EMS Pharma; ClinicalTrials.gov number, NCT04322123.).


Subject(s)
Antiviral Agents/administration & dosage , Azithromycin/administration & dosage , Coronavirus Infections/drug therapy , Hydroxychloroquine/administration & dosage , Pneumonia, Viral/drug therapy , Adult , Aged , Aged, 80 and over , Antiviral Agents/therapeutic use , Azithromycin/therapeutic use , Betacoronavirus , Brazil , COVID-19 , Drug Therapy, Combination , Female , Hospitalization , Humans , Hydroxychloroquine/therapeutic use , Male , Middle Aged , Pandemics , Patient Acuity , SARS-CoV-2 , Treatment Failure
20.
Ann Am Thorac Soc ; 17(10): 1257-1263, 2020 10.
Article in English | MEDLINE | ID: mdl-32526149

ABSTRACT

Rationale: Coated devices may reduce biofilm formation and reduce the occurrence of device-related infections in critically ill patients. A bundle of coated devices (an endotracheal tube [ETT], central venous catheter [CVC], and urinary catheter [UC]) simultaneously inserted may optimize benefits of coated devices in patients with the most severe illness.Objectives: To assess the feasibility of a randomized controlled trial on simultaneous insertion of gold/silver/palladium-coated devices versus uncoated devices in severely ill patients, which required sequential insertion of all three devices (an ETT, CVC, and UC) for support in the intensive care unit (ICU).Methods: This was a multicenter randomized controlled pilot trial. Patients who required simultaneous insertion of an ETT, CVC, and UC were randomized to treatment with coated versus uncoated devices, which were used as necessary for up to 28 days. The primary endpoint was feasibility, defined as the trial being able to enroll enough participants to have the sample size necessary for its secondary primary endpoint (estimating sepsis incidence in this population) in less than 1 year and for estimating the number of admitted patients who require simultaneous insertion of all three devices. Secondary endpoints included the incidence of sepsis and device-associated infections (ventilator-associated pneumonia, catheter-related bloodstream infection, and catheter-related urinary-tract infection) within each group as well as the number of days alive and free of antibiotics during the ICU stay. All events were adjudicated.Results: One hundred and three patients (48 in the coated-device group and 55 in the uncoated-device group) were included in the per-protocol analysis. The inclusion period was 8 months. There were 13 septic events in each group (26 in total), with an approximate incidence of sepsis of 32.3 (95% credible interval [CrI], 22.4-44.9) per 100 patient-days. The overall incidences of ventilator-associated pneumonia, catheter-related urinary-tract infection, and catheter-related bloodstream infection were 15.2 (95% CrI, 7.8-26.4), 6.3 (95% CrI, 2.4-13.7), and 7.9 (95% CrI, 3.6-15.1) per 1,000 patient-days, and incidence rates were not statistically different between groups. Patients in the coated-device group had more days alive and free of antibiotics in the ICU (28.97 d vs. 19.62 d per 100 patient-days; mean ratio, 1.48; 95% CrI, 1.16-1.89).Conclusions: Use of a bundle of coated devices as the initial treatment for of severely ill patients is feasible. Coated devices may be associated with more days alive and free of antibiotics.Clinical trial registered with www.clinicaltrials.gov (NCT03868241).


Subject(s)
Catheter-Related Infections , Catheterization, Central Venous , Cross Infection , Pneumonia, Ventilator-Associated , Catheter-Related Infections/epidemiology , Catheter-Related Infections/prevention & control , Catheterization, Central Venous/adverse effects , Cross Infection/epidemiology , Cross Infection/prevention & control , Humans , Intensive Care Units , Pilot Projects , Pneumonia, Ventilator-Associated/epidemiology , Pneumonia, Ventilator-Associated/prevention & control
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