IMPORTANCE: Therapeutic delivery of sodium nitrite during resuscitation improved survival in animal models of cardiac arrest, but efficacy has not been evaluated in clinical trials in humans. ...OBJECTIVE: To determine whether parenteral administration of sodium nitrite given by paramedics during resuscitation for out-of-hospital cardiac arrest improved survival to hospital admission. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, placebo-controlled, phase 2 randomized clinical trial including 1502 adults in King County, Washington, with out-of-hospital cardiac arrest from ventricular fibrillation or nonventricular fibrillation. Patients underwent resuscitation by paramedics and were enrolled between February 8, 2018, and August 19, 2019; follow-up and data abstraction were completed by December 31, 2019. INTERVENTIONS: Eligible patients with out-of-hospital cardiac arrest were randomized (1:1:1) to receive 45 mg of sodium nitrite (n = 500), 60 mg of sodium nitrite (n = 498), or placebo (n = 499), which was given via bolus injection by the paramedics as soon as possible during active resuscitation. MAIN OUTCOMES AND MEASURES: The primary outcome was survival to hospital admission and was evaluated with 1-sided hypothesis testing. The secondary outcomes included out-of-hospital variables (rate of return of spontaneous circulation, rate of rearrest, and use of norepinephrine to support blood pressure) and in-hospital variables (survival to hospital discharge; neurological outcomes at hospital discharge; cumulative survival to 24 hours, 48 hours, and 72 hours; and number of days in the intensive care unit). RESULTS: Among 1502 patients with out-of-hospital cardiac arrest who were randomized (mean age, 64 years SD, 17 years; 34% were women), 99% completed the trial. Overall, 205 patients (41%) in the 45 mg of sodium nitrite group and 212 patients (43%) in the 60 mg of sodium nitrite group compared with 218 patients (44%) in the placebo group survived to hospital admission; the mean difference for the 45-mg dose vs placebo was −2.9% (1-sided 95% CI, −8.0% to ∞; P = .82) and the mean difference for the 60-mg dose vs placebo was −1.3% (1-sided 95% CI, −6.5% to ∞; P = .66). None of the 7 prespecified secondary outcomes were significantly different, including survival to hospital discharge for 66 patients (13.2%) in the 45 mg of sodium nitrite group and 72 patients (14.5%) in the 60 mg of sodium nitrite group compared with 74 patients (14.9%) in the placebo group; the mean difference for the 45-mg dose vs placebo was −1.7% (2-sided 95% CI, −6.0% to 2.6%; P = .44) and the mean difference for the 60-mg dose vs placebo was −0.4% (2-sided 95% CI, −4.9% to 4.0%; P = .85). CONCLUSIONS AND RELEVANCE: Among patients with out-of-hospital cardiac arrest, administration of sodium nitrite, compared with placebo, did not significantly improve survival to hospital admission. These findings do not support the use of sodium nitrite during resuscitation from out-of-hospital cardiac arrest. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03452917
IMPORTANCE: Traumatic brain injury (TBI) is the leading cause of death and disability due to trauma. Early administration of tranexamic acid may benefit patients with TBI. OBJECTIVE: To determine ...whether tranexamic acid treatment initiated in the out-of-hospital setting within 2 hours of injury improves neurologic outcome in patients with moderate or severe TBI. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, double-blinded, randomized clinical trial at 20 trauma centers and 39 emergency medical services agencies in the US and Canada from May 2015 to November 2017. Eligible participants (N = 1280) included out-of-hospital patients with TBI aged 15 years or older with Glasgow Coma Scale score of 12 or less and systolic blood pressure of 90 mm Hg or higher. INTERVENTIONS: Three interventions were evaluated, with treatment initiated within 2 hours of TBI: out-of-hospital tranexamic acid (1 g) bolus and in-hospital tranexamic acid (1 g) 8-hour infusion (bolus maintenance group; n = 312), out-of-hospital tranexamic acid (2 g) bolus and in-hospital placebo 8-hour infusion (bolus only group; n = 345), and out-of-hospital placebo bolus and in-hospital placebo 8-hour infusion (placebo group; n = 309). MAIN OUTCOMES AND MEASURES: The primary outcome was favorable neurologic function at 6 months (Glasgow Outcome Scale-Extended score >4 moderate disability or good recovery) in the combined tranexamic acid group vs the placebo group. Asymmetric significance thresholds were set at 0.1 for benefit and 0.025 for harm. There were 18 secondary end points, of which 5 are reported in this article: 28-day mortality, 6-month Disability Rating Scale score (range, 0 no disability to 30 death), progression of intracranial hemorrhage, incidence of seizures, and incidence of thromboembolic events. RESULTS: Among 1063 participants, a study drug was not administered to 96 randomized participants and 1 participant was excluded, resulting in 966 participants in the analysis population (mean age, 42 years; 255 74% male participants; mean Glasgow Coma Scale score, 8). Of these participants, 819 (84.8%) were available for primary outcome analysis at 6-month follow-up. The primary outcome occurred in 65% of patients in the tranexamic acid groups vs 62% in the placebo group (difference, 3.5%; 90% 1-sided confidence limit for benefit, −0.9%; P = .16; 97.5% 1-sided confidence limit for harm, 10.2%; P = .84). There was no statistically significant difference in 28-day mortality between the tranexamic acid groups vs the placebo group (14% vs 17%; difference, −2.9% 95% CI, −7.9% to 2.1%; P = .26), 6-month Disability Rating Scale score (6.8 vs 7.6; difference, −0.9 95% CI, −2.5 to 0.7; P = .29), or progression of intracranial hemorrhage (16% vs 20%; difference, −5.4% 95% CI, −12.8% to 2.1%; P = .16). CONCLUSIONS AND RELEVANCE: Among patients with moderate to severe TBI, out-of-hospital tranexamic acid administration within 2 hours of injury compared with placebo did not significantly improve 6-month neurologic outcome as measured by the Glasgow Outcome Scale-Extended. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01990768
Paired serial limiting dilution assays Li, Xiudi; May, Susanne; Trumble, Ilana M. ...
Statistics in medicine,
30 October 2022, Volume:
41, Issue:
24
Journal Article
Peer reviewed
Serial limiting dilution (SLD) assays are a widely used tool in many areas of public health research to measure the concentration of target entities. This concentration can be estimated via maximum ...likelihood. Asymptotic as well as exact inference methods have been proposed for hypothesis testing and confidence interval construction in this one‐sample problem. However, in many scientific applications, it may be of interest to compare the concentration of target entities between a pair of samples and construct valid confidence intervals for the difference in concentrations. In this paper, an exact, computationally efficient inferential procedure is proposed for hypothesis testing and confidence interval construction in the two‐sample SLD assay problem. The proposed exact method is compared to an approach based on asymptotic approximations in simulation studies. The methods are illustrated using data from the University of North Carolina HIV Cure Center.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Grønnesby and Borgan (1996) propose an overall goodness-of-fit test for the Cox proportional hazards model. The basis of their test is a grouping of subjects by their estimated risk score. We show ...that the Grønnesby and Borgan test is algebraically identical to one obtained from adding group indicator variables to the model and testing the hypothesis the coefficients of the group indicator variables are zero via the score test. Thus showing that the test can be calculated using existing software. We demonstrate that the table of observed and estimated expected number of events within each group of the risk score is a useful adjunct to the test to help identify potential problems in fit.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Introduction
Despite prophylactic platelet transfusions, World Health Organization (WHO) grade ≥ 2 bleeding occurs in 50 to 70% of patients with hematologic malignancies and hypoproliferative ...thrombocytopenia secondary to therapy and/or underlying disease (Gernsheimer et al, Blood 2022). Anemia (hematocrit, HCT ≤ 25%), coagulopathy (activated partial thromboplastin time ≥ 30s, international normalized ratio ≥ 1.2), and platelet count ≤ 5000/µl were independently associated with increased risk of bleeding in the PLADO (platelet dose) trial of 1272 patients with hypoproliferative thrombocytopenia treated between 2004 to 2007 (Uhl et al, Blood 2017). Updated data on bleeding outcomes and risk of bleeding is lacking.
Methods
We performed a post-hoc analysis of bleeding outcomes and bleeding risk factors in 330 patients with hematologic malignancy and hypoproliferative thrombocytopenia from therapy and/or underlying disease randomized at 3 institutions to receive either tranexamic acid (TXA) or placebo in the double-blinded, multicenter American Trial to Evaluate Tranexamic Acid Therapy in Thrombocytopenia (A-TREAT) (Gernsheimer et al, Blood 2022). Patients received prophylactic platelet transfusions for a platelet count of ≤ 10,000/µl and WHO grade bleeding was assessed daily for 30 days after a platelet count ≤ 30,000/µl and study drug was started. Study drug was discontinued when platelet count was ≥ 30,000/ul for 46 hours without platelet transfusion support or until a maximum of 30 days after treatment activation, whichever came first. Red blood cell (RBC) transfusion was given according to local standard of care. Cox proportional hazards regression with time-varying covariates was used to assess the association of patient characteristics with the risk of a first major (grade 2+) bleeding event. HCT, platelet count, inpatient vs. outpatient status, steroid treatment, and fever were recorded daily. Patients were censored at the first of time of withdrawal, death, or day 30.
Results
WHO grade ≥ 2 bleeding occurred in 46% of patients overall with no difference between the TXA and placebo groups (TXA 44% versus placebo 47%, p=0.66). Bleeding rates were highest in allogeneic stem cell transplant patients, followed by chemotherapy, followed by autologous stem cell transplant. Overall bleeding rates by organ system showed oral and nasal (18%), skin (17%), gastrointestinal (11%), and genitourinary (11%) bleeding (Table 1). WHO grade ≥ 2 vaginal bleeding occurred in 28% of patients of childbearing potential despite widespread use of hormonal suppression.
In a proportional hazards regression model of time to first bleeding event, undergoing allogeneic stem cell transplant was associated with a non-significant increased hazard of bleeding vs chemotherapy (HR 1.32, 95% CI 0.92-1.89), whereas autologous transplant had significantly lower hazard of bleeding vs chemotherapy (HR 0.39, 95% CI 0.20-0.76) (Table 2). HCT < 21% was associated with increased bleeding risk even after adjusting for severe thrombocytopenia (HR 2.71, 29% CI 1.37, 5.36). Platelet count < 5000/µl was also associated with increased risk (HR 3.33, 95% CI 1.67-6.61). Inpatient status, presence of fever, and age did not significantly impact risk of first bleed.
Conclusions
The overall rate of WHO grade >2 bleeding was similar to historical literature with lower rates of gastrointestinal bleeding than previously reported (31% in PLADO). Vaginal bleeding was common despite standard use of hormonal suppression in patients of childbearing potential. Platelet count < 5000/µl remains a risk factor for bleeding. Regardless of platelet count, bleeding risk increased with HCT < 21% suggesting a red blood cell transfusion threshold higher than 21% is unlikely to mitigate bleeding. More investigation is needed on strategies to reduce bleeding in this patient population.
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IJS, IMTLJ, NUK, PNG, SAZU, UL, UM, UPUK, ZRSKP
IMPORTANCE: Pneumonia is the leading infectious killer of children. Rigorous evidence supporting antibiotic treatment of children with nonsevere fast-breathing pneumonia in low-resource African ...settings is lacking. OBJECTIVE: To assess whether treatment with placebo for nonsevere fast-breathing pneumonia is substantively less effective than 3 days of treatment with amoxicillin. DESIGN, SETTING, AND PARTICIPANTS: This double-blind, 2-arm, randomized clinical noninferiority trial with follow-up of 14 days screened 1343 HIV-uninfected children aged 2 to 59 months with nonsevere fast-breathing pneumonia at outpatient departments of hospitals in Lilongwe, Malawi, Africa, between June 2016 and June 2017. INTERVENTIONS: Placebo or amoxicillin dispersible tablets administered twice daily for 3 days. MAIN OUTCOMES AND MEASURES: The primary end point was the proportion of children failing treatment by day 4 with a relative noninferiority margin of 1.5 times the failure rate in the amoxicillin group. Primary analyses were performed based on the intention-to-treat principle. Planned secondary analyses included treatment failure or relapse by day 14. RESULTS: In total, 1126 children were randomized to 3 days of amoxicillin (n = 564) or placebo (n = 562) therapy. Baseline demographic and clinical characteristics were similar between the groups. For the entire study population, the mean (SD) age was 21.3 (15.1) months, and 601 (53.4%) were female. After an interim analysis, the data safety monitoring board stopped the study because children receiving amoxicillin had a 4.0% (22 of 552 with outcome data) treatment failure rate by day 4, whereas children receiving placebo had a 7.0% (38 of 543) treatment failure rate (adjusted relative risk, 1.78; 95% CI, 1.07%-2.97%; adjusted absolute difference, 3.0%; 95% CI, 0.4%-5.7%). Among children with known day 14 outcomes, 56 of 552 (10.1%) receiving amoxicillin and 64 of 543 (11.8%) receiving placebo had either treatment failure by day 4 or relapse by day 14 (relative risk, 1.16; 95% CI, 0.83%-1.63%; absolute difference, 1.6%; 95% CI, −2.1% to 5.4%). There were no deaths. CONCLUSIONS AND RELEVANCE: In HIV-uninfected children aged 2 to 59 months in a malaria-endemic region of Malawi, placebo treatment of nonsevere fast-breathing pneumonia was significantly inferior to treatment with amoxicillin. However, by day 4, approximately 93% of children receiving placebo were without treatment failure, and there was no significant difference between groups in treatment failure or relapse by day 14. The number of children with nonsevere fast-breathing pneumonia that needed amoxicillin treatment for 1 child to benefit was 33. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02760420
Out-of-hospital cardiac arrest (OHCA) survival varies greatly between communities. The Utstein template was developed and promulgated to improve the comparability of OHCA outcome reports, but it has ...undergone limited empiric validation. We sought to assess how much of the variation in OHCA survival between emergency medical services (EMS) across the globe is explained by differences in the Utstein factors. We also assessed how accurately the Utstein factors predict OHCA survival.
We performed a retrospective analysis of patient-level prospectively collected data from 12 OHCA registries from 12 countries for the period 1 Jan 2006 through 31 Dec 2011. We used generalized linear mixed models to examine the variation in survival between EMS agencies (n=232).
Twelve registries contributed 86,759 cases. Patient arrest characteristics, EMS treatment and patient outcomes varied across registries. Overall survival to hospital discharge was 10% (range, 6% to 22%). Overall survival with Cerebral Performance Category of 1 or 2 (available for 8/12 registries) was 8% (range, 2% to 20%). The area-under-the-curve for the Utstein model was 0.85 (Wald CI: 0.85–0.85). The Utstein factors explained 51% of the EMS agency variation in OHCA survival.
The Utstein factors explained 51% of the variation in survival to hospital discharge among multiple large geographically separate EMS agencies. This suggests that quality improvement and public health efforts should continue to target modifiable Utstein factors to improve OHCA survival. Further study is required to identify the reasons for the variation that is incompletely understood.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Children in Malawi with chest-indrawing pneumonia were randomly assigned to a 3-day or a 5-day regimen of amoxicillin. The 3-day regimen was noninferior to the 5-day regimen with respect to the ...incidence of treatment failure (5.9% vs. 5.2%). The frequency of adverse events was similar in the two groups.
Perishock pauses are pauses in chest compressions before and after defibrillatory shock. We examined the relationship between perishock pauses and survival to hospital discharge.
We included ...out-of-hospital cardiac arrest patients in the Resuscitation Outcomes Consortium Epistry-Cardiac Arrest who suffered arrest between December 2005 and June 2007, presented with a shockable rhythm (ventricular fibrillation or pulseless ventricular tachycardia), and had cardiopulmonary resuscitation process data for at least 1 shock (n=815). We used multivariable logistic regression to determine the association between survival and perishock pauses. In an analysis adjusted for Utstein predictors of survival, the odds of survival were significantly lower for patients with preshock pause ≥20 seconds (odds ratio, 0.47; 95% confidence interval, 0.27 to 0.82) and perishock pause ≥40 seconds (odds ratio, 0.54; 95% confidence interval, 0.31 to 0.97) compared with patients with preshock pause <10 seconds and perishock pause <20 seconds. Postshock pause was not independently associated with a significant change in the odds of survival. Log-linear modeling depicted a decrease in survival to hospital discharge of 18% and 14% for every 5-second increase in both preshock and perishock pause interval (up to 40 and 50 seconds, respectively), with no significant association noted with changes in the postshock pause interval.
In patients with cardiac arrest presenting in a shockable rhythm, longer perishock and preshock pauses were independently associated with a decrease in survival to hospital discharge. The impact of preshock pause on survival suggests that refinement of automatic defibrillator software and paramedic education to minimize preshock pause delays may have a significant impact on survival.
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