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1.
JAMA ; 2020 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-33165621

RESUMO

Importance: Data on the efficacy of hydroxychloroquine for the treatment of coronavirus disease 2019 (COVID-19) are needed. Objective: To determine whether hydroxychloroquine is an efficacious treatment for adults hospitalized with COVID-19. Design, Setting, and Participants: This was a multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US. Adults hospitalized with respiratory symptoms from severe acute respiratory syndrome coronavirus 2 infection were enrolled between April 2 and June 19, 2020, with the last outcome assessment on July 17, 2020. The planned sample size was 510 patients, with interim analyses planned after every 102 patients were enrolled. The trial was stopped at the fourth interim analysis for futility with a sample size of 479 patients. Interventions: Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237). Main Outcomes and Measures: The primary outcome was clinical status 14 days after randomization as assessed with a 7-category ordinal scale ranging from 1 (death) to 7 (discharged from the hospital and able to perform normal activities). The primary outcome was analyzed with a multivariable proportional odds model, with an adjusted odds ratio (aOR) greater than 1.0 indicating more favorable outcomes with hydroxychloroquine than placebo. The trial included 12 secondary outcomes, including 28-day mortality. Results: Among 479 patients who were randomized (median age, 57 years; 44.3% female; 37.2% Hispanic/Latinx; 23.4% Black; 20.1% in the intensive care unit; 46.8% receiving supplemental oxygen without positive pressure; 11.5% receiving noninvasive ventilation or nasal high-flow oxygen; and 6.7% receiving invasive mechanical ventilation or extracorporeal membrane oxygenation), 433 (90.4%) completed the primary outcome assessment at 14 days and the remainder had clinical status imputed. The median duration of symptoms prior to randomization was 5 days (interquartile range [IQR], 3 to 7 days). Clinical status on the ordinal outcome scale at 14 days did not significantly differ between the hydroxychloroquine and placebo groups (median [IQR] score, 6 [4-7] vs 6 [4-7]; aOR, 1.02 [95% CI, 0.73 to 1.42]). None of the 12 secondary outcomes were significantly different between groups. At 28 days after randomization, 25 of 241 patients (10.4%) in the hydroxychloroquine group and 25 of 236 (10.6%) in the placebo group had died (absolute difference, -0.2% [95% CI, -5.7% to 5.3%]; aOR, 1.07 [95% CI, 0.54 to 2.09]). Conclusions and Relevance: Among adults hospitalized with respiratory illness from COVID-19, treatment with hydroxychloroquine, compared with placebo, did not significantly improve clinical status at day 14. These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized adults. Trial Registration: ClinicalTrials.gov: NCT04332991.

2.
JAMA Netw Open ; 3(11): e2025815, 2020 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-33196808

RESUMO

Importance: State decisions not to expand Medicaid under the Patient Protection and Affordable Care Act could reduce emergency access to acute care hospitals. Objective: To determine the relationship between state Medicaid expansion and emergency access to acute care hospitals in the United States. Design, Setting, and Participants: This cross-sectional study linked hospital-level data from the Centers for Medicare & Medicaid Services from 2007 to 2017 to US Census data for all 50 US states and the District of Columbia. Geospatial analyses and difference-in-differences regression models were used to compare temporal changes in the size of the population without 30-minute access to acute care hospitals between 32 states that expanded Medicaid with the population without access in 19 that did not, before and after expansion. Analyses focused on the total population and those with low incomes; secondary analyses examined emergency access to safety-net hospitals. Exposures: State-level Medicaid expansion. Main Outcomes and Measures: Population without emergency access to an acute care hospital, defined as living outside a 30-minute drive of any hospital. Results: States that did not expand Medicaid experienced an increase in the population without access to hospitals overall (without expansion: 6.76% to 6.79% [0.03%]; vs with expansion: 5.65% to 5.35% [-0.30%]; difference-in-differences, 0.33%; 95% CI, 0.33%-0.34%; P < .001) and for low-income persons (without expansion: 7.43% to 7.39% [-0.04%]; vs with expansion: 6.25% to 6.15% [-0.10%]; difference-in-differences, 0.06%; 95% CI, 0.05%-0.07%; P < .001). If access changes in nonexpansion states were the same as expansion states, an estimated 421 000 more persons overall and 48 000 more low-income persons would have retained access. States that did not expand Medicaid experienced an increase in the population without access to safety-net hospitals overall (46.91% to 47.70% [0.79%] vs 33.94% to 33.07% [-0.87%]; difference-in-differences, 1.66%; 95% CI, 1.64%-1.66%; P < .001) and for low-income persons (45.28% to 46.14% [0.86%] vs 33.00% to 32.23% [-0.77%]; difference-in-differences, 1.63%; 95% CI, 1.63%-1.67%; P < .001). If access changes in nonexpansion states were the same as expansion states, an estimated 2 242 000 more persons overall and 364 000 more low-income persons would have retained access. Conclusions and Relevance: States that did not expand Medicaid under the Patient Protection and Affordable Care Act were associated with worse emergency access to acute care hospitals compared with states that expanded Medicaid.

3.
PLoS One ; 15(11): e0241122, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33151963

RESUMO

Sepsis is the leading cause of death in hospitalized patients and beyond the hospital stay and these long-term sequelae are due in part to unresolved inflammation. Metabolic shift from oxidative phosphorylation to aerobic glycolysis links metabolism to inflammation and such a shift is commonly observed in sepsis under normoxic conditions. By shifting the metabolic state from aerobic glycolysis to oxidative phosphorylation, we hypothesized it would reverse unresolved inflammation and subsequently improve outcome. We propose a shift from aerobic glycolysis to oxidative phosphorylation as a sepsis therapy by targeting the pathways involved in the conversion of pyruvate into acetyl-CoA via pyruvate dehydrogenase (PDH). Chemical manipulation of PDH using dichloroacetic acid (DCA) will promote oxidative phosphorylation over glycolysis and decrease inflammation. We tested our hypothesis in a Drosophila melanogaster model of surviving sepsis infected with Staphylococcus aureus. Drosophila were divided into 3 groups: unmanipulated, sham and sepsis survivors, all treated with linezolid; each group was either treated or not with DCA for one week following sepsis. We followed lifespan, measured gene expression of Toll, defensin, cecropin A, and drosomycin, and levels of lactate, pyruvate, acetyl-CoA as well as TCA metabolites. In our model, metabolic effects of sepsis are modified by DCA with normalized lactate, TCA metabolites, and was associated with improved lifespan of sepsis survivors, yet had no lifespan effects on unmanipulated and sham flies. While Drosomycin and cecropin A expression increased in sepsis survivors, DCA treatment decreased both and selectively increased defensin.

4.
JAMA ; 324(13): 1317-1329, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32876697

RESUMO

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.


Assuntos
Anti-Inflamatórios/administração & dosagem , Infecções por Coronavirus/tratamento farmacológico , Hidrocortisona/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Respiração Artificial/estatística & dados numéricos , Corticosteroides/uso terapêutico , Adulto , Anti-Inflamatórios/efeitos adversos , Betacoronavirus , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/terapia , Término Precoce de Ensaios Clínicos , Feminino , Humanos , Hidrocortisona/efeitos adversos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/terapia , Choque/tratamento farmacológico , Choque/etiologia , Resultado do Tratamento
5.
BMJ Open ; 10(9): e037690, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32994242

RESUMO

INTRODUCTION: As the population ages, there is interest in strategies to promote resiliency, especially for frail patients at risk of its complications. The physiological stress of surgery in high-risk individuals has been proposed both as an important cause of accelerated age-related decline in health and as a model testing the effectiveness of strategies to improve resiliency to age-related health decline. We describe a randomised, embedded, multifactorial, adaptative platform (REMAP) trial to investigate multiple perioperative interventions, the first of which is metformin and selected for its anti-inflammatory and anti-ageing properties beyond its traditional blood glucose control features. METHODS AND ANALYSIS: Within a multihospital, single healthcare system, the Core Protocol for Strategies to Promote ResiliencY (SPRY) will be embedded within both the electronic health record (EHR) and the healthcare culture generating a continuously self-learning healthcare system. Embedding reduces the administrative burden of a traditional trial while accessing and rapidly analysing routine patient care EHR data. SPRY-Metformin is a placebo-controlled trial and is the first SPRY domain evaluating the effectiveness of three metformin dosages across three preoperative durations within a heterogeneous set of major surgical procedures. The primary outcome is 90-day hospital-free days. Bayesian posterior probabilities guide interim decision-making with predefined rules to determine stopping for futility or superior dosing selection. Using response adaptative randomisation, a maximum of 2500 patients allows 77%-92% power, detecting >15% primary outcome improvement. Secondary outcomes include mortality, readmission and postoperative complications. A subset of patients will be selected for substudies evaluating the microbiome, cognition, postoperative delirium and strength. ETHICS AND DISSEMINATION: The Core Protocol of SPRY REMAP and associated SPRY-Metformin Domain-Specific Appendix have been ethically approved by the Institutional Review Board and are publicly registered. Results will be publicly available to healthcare providers, patients and trial participants following achieving predetermined platform conclusions. TRIAL REGISTRATION NUMBER: NCT03861767.

6.
J Thromb Haemost ; 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32888372

RESUMO

INTRODUCTION: Coronavirus disease (COVID-19) is associated with a high incidence of thrombosis and mortality despite standard anticoagulant thromboprophylaxis. There is equipoise regarding the optimal dose of anticoagulant intervention in hospitalized patients with COVID-19 and consequently, immediate answers from high-quality randomized trials are needed. METHODS: The World Health Organization's International Clinical Trials Registry Platform was searched on June 17, 2020 for randomized controlled trials comparing increased dose to standard dose anticoagulant interventions in hospitalized COVID-19 patients. Two authors independently screened the full records for eligibility and extracted data in duplicate. RESULTS: A total of 20 trials were included in the review. All trials are open label, 5 trials use an adaptive design, 1 trial uses a factorial design, 2 trials combine multi-arm parallel group and factorial designs in flexible platform trials, and at least 15 trials have multiple study sites. With individual target sample sizes ranging from 30 to 3000 participants, the pooled sample size of all included trials is 12 568 participants. Two trials include only intensive care unit patients, and 10 trials base patient eligibility on elevated D-dimer levels. Therapeutic intensity anticoagulation is evaluated in 14 trials. All-cause mortality is part of the primary outcome in 14 trials. DISCUSSION: Several trials evaluate different dose regimens of anticoagulant interventions in hospitalized patients with COVID-19. Because these trials compete for sites and study participants, a collaborative effort is needed to complete trials faster, conduct pooled analyses and bring effective interventions to patients more quickly.

7.
JAMA ; 324(13): 1330-1341, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32876694

RESUMO

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.


Assuntos
Corticosteroides/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Glucocorticoides/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Betacoronavirus , Causas de Morte , Infecções por Coronavirus/mortalidade , Estado Terminal , Dexametasona/uso terapêutico , Humanos , Hidrocortisona/uso terapêutico , Metilprednisolona/uso terapêutico , Pandemias , Pneumonia Viral/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto
9.
Trials ; 21(1): 734, 2020 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-32831155

RESUMO

OBJECTIVES: Primary objective: To estimate the effect of corticosteroids compared with usual care or placebo on mortality up to 28 days after randomization. Secondary objectives: To examine whether the effect of corticosteroids compared with usual care or placebo on mortality up to 28 days after randomization varies between subgroups related to treatment characteristics, disease severity at the time of randomization, patient characteristics, or risk of bias. To examine the effect of corticosteroids compared with usual care or placebo on serious adverse events. STUDY DESIGN: Prospective meta-analysis of randomized controlled trials. Both placebo-controlled and open-label trials are eligible. PARTICIPANTS: Hospitalised, critically ill patients with suspected or confirmed COVID-19. INTERVENTION AND COMPARATOR: Intervention groups will have received therapeutic doses of a steroid (dexamethasone, hydrocortisone or methylprednisolone) with IV or oral administration immediately after randomization. The comparator groups will have received standard of care or usual care or placebo. MAIN OUTCOME: All-cause mortality up to 28 days after randomization. SEARCH METHODS: Systematic searching of clinicaltrials.gov , EudraCT, the WHO ISRCTN registry, and the Chinese clinical trials registry. Additionally, research and WHO networks will be asked for relevant trials. RISK OF BIAS ASSESSMENTS: These will be based on the Cochrane RoB 2 tool, and will use structured information provided by the trial investigators on a form designed for this prospective meta-analysis. We will use GRADE to assess the certainty of the evidence. STATISTICAL ANALYSES: Trial investigators will provide data on the numbers of participants who did and did not experience each outcome according to intervention group, overall and in specified subgroups. We will conduct fixed-effect (primary analysis) and random-effects (Paule-Mandel estimate of heterogeneity and Hartung-Knapp adjustment) meta-analyses. We will quantify inconsistency in effects between trials using I2 statistics. Evidence for subgroup effects will be quantified by ratios of odds ratios comparing effects in the subgroups, and corresponding interaction p-values. Comparisons between subgroups defined by trial characteristics will be made using random-effects meta-regression. Comparisons between subgroups defined by patient characteristics will be made by estimating trial-specific ratios of odds ratios comparing intervention effects between subgroups then combining these using random-effects meta-analysis. Steroid interventions will be classified as high or low dose according to whether the dose is greater or less than or equal to 400 mg hydrocortisone per day or equivalent. We will use network meta-analysis methods to make comparisons between the effects of high and low dose steroid interventions (because one trial randomized participants to both low and high dose steroid arms). PROSPERO REGISTRATION NUMBER: CRD42020197242 FULL PROTOCOL: The full protocol for this prospective meta-analysis is attached as an additional file, accessible from the Trials website (Additional file 1). To expedite dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol for the systematic review.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Glucocorticoides/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Corticosteroides/uso terapêutico , Betacoronavirus , Estado Terminal , Dexametasona/uso terapêutico , Humanos , Hidrocortisona/uso terapêutico , Metilprednisolona/uso terapêutico , Pandemias , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
Resuscitation ; 2020 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-32653571

RESUMO

AIM: Children surviving cardiac arrest are at high risk of neurological morbidity and mortality; however, there is a lack of validated prognostic biomarkers. We aimed to evaluate brain magnetic resonance imaging (MRI) and spectroscopy (MRS) as predictors of death and disability. Secondly, we evaluated whether MRI/S by randomized group. METHODS: This single center study analyzed clinically indicated brain MRI/S data from children enrolled in a randomized controlled trial of 24 vs. 72 h of hypothermia following cardiac arrest. Two pediatric radiologists scored conventional MRIs. Lactate and N-acetyl-aspartate (NAA) concentrations (mmol/kg) were determined from spectra acquired from the basal ganglia, thalamus, parietal white matter and parietooccipital gray matter. Mortality and neurological outcomes (favorable = Pediatric Cerebral Performance Category [PCPC] 1, 2, 3 or increase < 2) were assessed at hospital discharge. Non-parametric tests were used to test for associations between MRI/S biomarkers and outcome and randomized group. RESULTS: 23 children with (median [interquartile range]) age of 1.5 (0.3-4.0) years. Ten (44%) had favorable outcome. There were more T2 brain lesions in the lentiform nuclei in children with unfavorable 12 (92%) vs. favorable 3 (33%) outcome, p = 0.007. Increased lactate and decreased NAA concentrations in the parietooccipital gray matter and decreased NAA in the parietal white matter were associated with unfavorable outcome (p's < 0.05). There were no differences for any biomarker by randomized group. CONCLUSION: Regional cerebral and metabolic MRI/S biomarkers are predictive of neurological outcomes at hospital discharge in pediatric cardiac arrest and should undergo validation testing in a large sample.

11.
Crit Care ; 24(1): 461, 2020 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-32718333

RESUMO

INTRODUCTION: Pneumonia is the most common cause of mortality from infectious diseases, the second leading cause of nosocomial infection, and the leading cause of mortality among hospitalized adults. To improve clinical management, metabolomics has been increasingly applied to find specific metabolic biopatterns (profiling) for the diagnosis and prognosis of various infectious diseases, including pneumonia. METHODS: One hundred fifty bacterial community-acquired pneumonia (CAP) patients whose plasma samples were drawn within the first 24 h of hospital admission were enrolled in this study and separated into two age- and sex-matched cohorts: non-survivors (died ≤ 90 days) and survivors (survived > 90 days). Three analytical tools, 1H-NMR spectroscopy, GC-MS, and targeted DI-MS/MS, were used to prognosticate non-survivors from survivors by means of metabolic profiles. RESULTS: We show that quantitative lipid profiling using DI-MS/MS can predict the 90-day mortality and in-hospital mortality among patients with bacterial CAP compared to 1H-NMR- and GC-MS-based metabolomics. This study showed that the decreased lysophosphatidylcholines and increased acylcarnitines are significantly associated with increased mortality in bacterial CAP. Additionally, we found that decreased lysophosphatidylcholines and phosphatidylcholines (> 36 carbons) and increased acylcarnitines may be used to predict the prognosis of in-hospital mortality for bacterial CAP as well as the need for ICU admission and severity of bacterial CAP. DISCUSSION: This study demonstrates that lipid-based plasma metabolites can be used for the prognosis of 90-day mortality among patients with bacterial CAP. Moreover, lipid profiling can be utilized to identify patients with bacterial CAP who are at the highest risk of dying in hospital and who need ICU admission as well as the severity assessment of CAP.

12.
Pediatrics ; 146(1)2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32605994

RESUMO

BACKGROUND: In 2013, New York introduced regulations mandating that hospitals develop pediatric-specific protocols for sepsis recognition and treatment. METHODS: We used hospital discharge data from 2011 to 2015 to compare changes in pediatric sepsis outcomes in New York and 4 control states: Florida, Massachusetts, Maryland, and New Jersey. We examined the effect of the New York regulations on 30-day in-hospital mortality using a comparative interrupted time-series approach, controlling for patient and hospital characteristics and preregulation temporal trends. RESULTS: We studied 9436 children admitted to 237 hospitals. Unadjusted pediatric sepsis mortality decreased in both New York (14.0% to 11.5%) and control states (14.4% to 11.2%). In the primary analysis, there was no significant effect of the regulations on mortality trends (differential quarterly change in mortality in New York compared with control states: -0.96%; 95% confidence interval [CI]: -1.95% to 0.02%; P = .06). However, in a prespecified sensitivity analysis excluding metropolitan New York hospitals that participated in earlier sepsis quality improvement, the regulations were associated with improved mortality trends (differential change: -2.08%; 95% CI: -3.79% to -0.37%; P = .02). The regulations were also associated with improved mortality trends in several prespecified subgroups, including previously healthy children (differential change: -1.36%; 95% CI: -2.62% to -0.09%; P = .04) and children not admitted through the emergency department (differential change: -2.42%; 95% CI: -4.24% to -0.61%; P = .01). CONCLUSIONS: Implementation of statewide sepsis regulations was generally associated with improved mortality trends in New York State, particularly in prespecified subpopulations of patients, suggesting that the regulations were successful in affecting sepsis outcomes.


Assuntos
Avaliação de Resultados em Cuidados de Saúde , Sepse/mortalidade , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Mortalidade Hospitalar , Humanos , Lactente , Análise de Séries Temporais Interrompida , Masculino , Avaliação de Resultados em Cuidados de Saúde/legislação & jurisprudência , Estudos Retrospectivos , Sepse/diagnóstico , Sepse/terapia , Estados Unidos/epidemiologia
15.
N Engl J Med ; 382(26): 2579, 2020 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-32579826
17.
Artigo em Inglês | MEDLINE | ID: mdl-32584598

RESUMO

RATIONALE: Urinary tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) can predict AKI in patients with sepsis. OBJECTIVES: Since most sepsis patients present with AKI, critical questions are whether biomarkers can inform on the response to treatment and whether they might be used to guide therapy. METHODS: We measured [TIMP-2]•[IGFBP7] before and after a 6-hour resuscitation in 688 patients with septic shock enrolled in the ProCESS trial. Our primary endpoint was stage 3 AKI, renal replacement therapy or death within 7 days. MEASUREMENTS AND MAIN RESULTS: The endpoint was reached in 113 patients (16.4%). In patients with negative [TIMP-2]•[IGFBP7] at baseline, those who became positive (>0.3 units) after resuscitation had 3-times higher risk compared to those who remained negative (21.8% vs 8.5%, p=0.01; OR 3.0, 95%CI 1.31-6.87). Conversely, compared to patients with a positive biomarker at baseline that were still positive at hour 6, risk was reduced for patients who became negative (23.8% vs 9.8%, p=0.01; OR 2.15, 95%CI 1.17-3.95). A positive [TIMP-2]•[IGFBP7] following resuscitation was associated with worse outcomes in both patients with and without AKI at that time point. Clinical response to resuscitation, as judged by APACHE II score, was weakly predictive of the endpoint (AUC 0.68, 95%CI 0.62-0.73) and improved with addition of [TIMP-2]•[IGFBP7] (0.72, 95%CI 0.66-0.77 p=0.03). Different resuscitation protocols did not alter biomarker trajectories, nor outcomes in biomarker positive or negative patients. However, biomarker trajectories were associated with outcome. CONCLUSIONS: Changes in urinary [TIMP-2]•[IGFBP7] following initial fluid resuscitation identify sepsis patients with differing risk for progression of AKI. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT00510835.

18.
BMJ Open ; 10(3): e033521, 2020 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-32229520

RESUMO

INTRODUCTION: Although shortcomings in clinician-family communication and decision making for incapacitated, critically ill patients are common, there are few rigorously tested interventions to improve outcomes. In this manuscript, we present our methodology for the Pairing Re-engineered Intensive Care Unit Teams with Nurse-Driven Emotional support and Relationship Building (PARTNER 2) trial, and discuss design challenges and their resolution. METHODS AND ANALYSIS: This is a pragmatic, stepped-wedge, cluster randomised controlled trial comparing the PARTNER 2 intervention to usual care among 690 incapacitated, critically ill patients and their surrogates in five ICUs in Pennsylvania. Eligible subjects will include critically ill patients at high risk of death and/or severe long-term functional impairment, their main surrogate decision-maker and their clinicians. The PARTNER intervention is delivered by the interprofessional ICU team and overseen by 4-6 nurses from each ICU. It involves: (1) advanced communication skills training for nurses to deliver support to surrogates throughout the ICU stay; (2) deploying a structured family support pathway; (3) enacting strategies to foster collaboration between ICU and palliative care services and (4) providing intensive implementation support to each ICU to incorporate the family support pathway into clinicians' workflow. The primary outcome is surrogates' ratings of the quality of communication during the ICU stay as assessed by telephone at 6-month follow-up. Prespecified secondary outcomes include surrogates' scores on the Hospital Anxiety and Depression Scale, the Impact of Event Scale, the modified Patient Perception of Patient Centredness scale, the Decision Regret Scale, nurses' scores on the Maslach Burnout Inventory, and length of stay during and costs of the index hospitalisation.We also discuss key methodological challenges, including determining the optimal level of randomisation, using existing staff to deploy the intervention and maximising long-term follow-up of participants. ETHICS AND DISSEMINATION: We obtained ethics approval through the University of Pittsburgh, Human Research Protection Office. The findings will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02445937.

19.
JAMA Netw Open ; 3(3): e201742, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32227179

RESUMO

Importance: There is limited evidence regarding how patients make choices in advance directives (ADs) or whether these choices influence subsequent care. Objective: To examine whether default options in ADs influence care choices and clinical outcomes. Design, Setting, and Participants: This randomized clinical trial included 515 patients who met criteria for having serious illness and agreed to participate. Patients were enrolled at 20 outpatient clinics affiliated with the University of Pennsylvania Health System and the University of Pittsburgh Medical Center from February 2014 to April 2016 and had a median follow-up of 18 months. Data analysis was conducted from November 2018 to April 2019. Interventions: Patients were randomly assigned to complete 1 of the 3 following ADs: (1) a comfort-promoting plan of care and nonreceipt of potentially life-sustaining therapies were selected by default (comfort AD), (2) a life-extending plan of care and receipt of potentially life-sustaining therapies were selected by default (life-extending AD), or (3) no choices were preselected (standard AD). Main Outcomes and Measures: This trial was powered to rule out a reduction in hospital-free days in the intervention groups. Secondary outcomes included choices in ADs for an overall comfort-oriented approach to care, choices to forgo 4 forms of life support, patients' quality of life, decision conflict, place of death, admissions to hospitals and intensive care units, and costs of inpatient care. Results: Among 515 patients randomized, 10 withdrew consent and 13 were later found to be ineligible, leaving 492 (95.5%) in the modified intention-to-treat (mITT) sample (median [interquartile range] age, 63 [56-70] years; 279 [56.7%] men; 122 [24.8%] black; 363 [73.8%] with cancer). Of these, 264 (53.7%) returned legally valid ADs and were debriefed about their assigned intervention. Among these, patients completing comfort ADs were more likely to choose comfort care (54 of 85 [63.5%]) than those returning standard ADs (45 of 91 [49.5%]) or life-extending ADs (33 of 88 [37.5%]) (P = .001). Among 492 patients in the mITT sample, 57 of 168 patients [33.9%] who completed the comfort AD, 47 of 165 patients [28.5%] who completed the standard AD, and 35 of 159 patients [22.0%] who completed the life-extending AD chose comfort care (P = .02), with patients not returning ADs coded as not selecting comfort care. In mITT analyses, median (interquartile range) hospital-free days among 168 patients assigned to comfort ADs and 159 patients assigned to life-extending default ADs were each noninferior to those among 165 patients assigned to standard ADs (standard AD: 486 [306-717] days; comfort AD: 554 [296-833] days; rate ratio, 1.05; 95% CI, 0.90-1.23; P < .001; life-extending AD: 550 [325-783] days; rate ratio, 1.03; 95% CI, 0.88-1.20; P < .001). There were no differences among groups in other secondary outcomes. Conclusions and Relevance: In this randomized clinical trial, default options in ADs altered the choices seriously ill patients made regarding their future care without changing clinical outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02017548.


Assuntos
Diretivas Antecipadas , Tomada de Decisões , Qualidade de Vida , Assistência Terminal , Diretivas Antecipadas/psicologia , Diretivas Antecipadas/estatística & dados numéricos , Idoso , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Paliativos , Planejamento de Assistência ao Paciente , Satisfação do Paciente , Pennsylvania , Assistência Terminal/psicologia , Assistência Terminal/estatística & dados numéricos
20.
JAMA Surg ; 155(6): e200416, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32267474

RESUMO

Importance: Adults with comorbidity have less physiological reserve and an increased rate of postoperative mortality and readmission after the stress of a major surgical intervention. Objective: To assess postoperative mortality and readmission among individuals with diabetes with or without preoperative prescriptions for metformin. Design, Setting, and Participants: This cohort study obtained data from the electronic health record of a multicenter, single health care system in Pennsylvania. Included were adults with diabetes who underwent a major operation with hospital admission from January 1, 2010, to January 1, 2016, at 15 community and academic hospitals within the system. Individuals without a clinical indication for metformin therapy were excluded. Follow-up continued until December 18, 2018. Exposures: Preoperative metformin exposure was defined as 1 or more prescriptions for metformin in the 180 days before the surgical procedure. Main Outcomes and Measures: All-cause postoperative mortality, hospital readmission within 90 days of discharge, and preoperative inflammation measured by the neutrophil to leukocyte ratio were compared between those with and without preoperative prescriptions for metformin. The corresponding absolute risk reduction (ARR) and adjusted hazard ratio (HR) with 95% CI were calculated in a propensity score-matched cohort. Results: Among the 10 088 individuals with diabetes who underwent a major surgical intervention, 5962 (59%) had preoperative metformin prescriptions. A total of 5460 patients were propensity score-matched, among whom the mean (SD) age was 67.7 (12.2) years, and 2866 (53%) were women. In the propensity score-matched cohort, preoperative metformin prescriptions were associated with a reduced hazard for 90-day mortality (adjusted HR, 0.72 [95% CI, 0.55-0.95]; ARR, 1.28% [95% CI, 0.26-2.31]) and hazard of readmission, with mortality as a competing risk at both 30 days (ARR, 2.09% [95% CI, 0.35-3.82]; sub-HR, 0.84 [95% CI, 0.72-0.98]) and 90 days (ARR, 2.78% [95% CI, 0.62-4.95]; sub-HR, 0.86 [95% CI, 0.77-0.97]). Preoperative inflammation was reduced in those with metformin prescriptions compared with those without (mean neutrophil to leukocyte ratio, 4.5 [95% CI, 4.3-4.6] vs 5.0 [95% CI, 4.8-5.3]; P < .001). E-value analysis suggested robustness to unmeasured confounding. Conclusions and Relevance: This study found an association between metformin prescriptions provided to individuals with type 2 diabetes before a major surgical procedure and reduced risk-adjusted mortality and readmission after the operation. This association warrants further investigation.

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