Urinary Chloride Excretion Postcardiopulmonary Bypass in Pediatric Patients-A Pilot Study.

The aim of this study was to describe renal chloride metabolism following cardiopulmonary bypass (CPB) surgery in pediatric patients. A prospective observational trial in a tertiary pediatric intensive care unit (PICU) with 20 recruited patients younger than 2 years following CPB surgery was conducted. Urinary electrolytes, plasma urea, electrolytes, creatinine, and arterial blood gases were collected preoperatively, on admission to PICU and at standardized intervals thereafter. The urinary and plasma strong ion differences (SID) were calculated from these results at each time point. Fluid input and output and electrolyte and drug administration were also recorded. Median chloride administration was 67.7 mmol/kg over the first 24 hours. Urinary chloride (mmol/L; median interquartile range [IQR]) was 30 (19, 52) prior to surgery, 15 (15, 65) on admission, and remained below baseline until 24 hours. Plasma chloride (mmol/L; median [IQR]) was 105 (98, 107) prior to surgery and 101 (101, 106) on admission to PICU. It then increased from baseline, but remained within normal limits, for the remainder of the study. The urinary SID increased from 49.8 (19.1, 87.2) preoperatively to a maximum of 122.7 (92.5, 151.8) at 6 hours, and remained elevated until 48 hours. Plasma and urinary chloride concentrations were not associated with the development of acute kidney injury. Urinary chloride excretion is impaired after CPB. The urinary SID increase associated with the decrease in chloride excretion suggests impaired production and/or excretion of ammonium by the nephron following CPB, with gradual recovery postoperatively.

Diabetes and COVID-19 Outcomes: An Analysis of Freeman Health System Patients.

BACKGROUND: As COVID-19 continues to affect millions of people around the world, it has become vital to understand how comorbidities such as diabetes affect the health outcomes of these patients. While earlier studies have focused on major metropolitan areas, rural settings have been comparatively understudied. The goal of this study is to understand the effect on mortality that these two diseases have in the inpatient setting of a rural population. METHODS: The electronic medical records of all adult patients admitted to Freeman Health System, Joplin, Missouri, United States, between April 1, 2020, and December 31, 2021, were reviewed for the presence of COVID-19 infection and/or diabetes (type I and type II). Freeman Health is a major health system headquartered in Southwest Missouri. Diagnoses were obtained through the use of standard International Classification of Disease, 10th edition (ICD-10) codes. The initial data set consisted of 19,323 admissions. After excluding duplicate admissions and those who had already been infected with COVID-19, 1,729 patients with COVID-19, 172 patients with type I diabetes, and 3,992 patients with type II diabetes were included in the analysis of inpatient all-cause mortality. We hypothesized that patients with type I and type II diabetes would both show an increased risk of all-cause mortality. Mortality in the context of our study results refers to all-cause mortality. RESULTS: The all-cause mortality rate was 19.94% (137/687, with a 95% confidence interval (CI) of 16.95%-22.93%) in patients admitted with both diabetes (the combined type I and type II subsets) and COVID-19 (P1). The mortality rate was 16.03% (167/1042, with 95% CI of 13.80%-18.25%) in patients admitted with COVID-19 who did not have diabetes (P2). Patients admitted with a comorbid diagnosis of diabetes but without COVID-19 (P5) had a much lower mortality rate of 5.98% (249/4164, with a 95% CI of 5.26%-6.70%). The combination of both COVID-19 and diabetes together was associated with a higher mortality rate than either of the two separately. The mortality rate was additionally elevated in patients with both type II diabetes and COVID-19 (P4) (134/663, mortality rate of 20.21% with 95% CI of 17.15%-23.27%) versus those with COVID-19 without diabetes (P2) (167/1042, 16.03% with 95% CI of 13.80%-18.25%), an overall difference of 4.18% (95% CI of 0.40%-7.94%). The subset of patients with type I diabetes with COVID-19 (P3) and type I diabetes without COVID-19 (P6) were too small to accurately power individual analysis. The subset of patients with diabetes (type I and type II) and without COVID-19 (P5) had the lowest mortality rate of any subset adequately powered for analysis at 5.98% (249/41464, CI of 5.26%-6.70%).  Conclusions: The results of this study show that type II diabetes is a significant risk factor for mortality in admitted COVID-19 patients. P4 had the highest overall mortality of any subset studied. The study was underpowered to show if type I diabetes patients, with and without COVID-19, had an increased mortality when analyzed separately. COVID-19 significantly increased mortality in all subsets adequately powered for full analysis.

Assessing the impact of risk-based data monitoring on outcomes for a paediatric multicentre randomised controlled trial.

BACKGROUND/AIMS: Regulatory guidelines recommend that sponsors develop a risk-based approach to monitoring clinical trials. However, there is a lack of evidence to guide the effective implementation of monitoring activities encompassed in this approach. The aim of this study was to assess the efficiency and impact of the risk-based monitoring approach used for a multicentre randomised controlled trial comparing treatments in paediatric patients undergoing cardiac bypass surgery. METHODS: This is a secondary analysis of data from a randomised controlled trial that implemented targeted source data verification as part of the risk-based monitoring approach. Monitoring duration and source to database error rates were calculated across the monitored trial dataset. The monitored and unmonitored trial dataset, and simulated trial datasets with differing degrees of source data verification and cohort sizes were compared for their effect on trial outcomes. RESULTS: In total, 106,749 critical data points across 1,282 participants were verified from source data either remotely or on-site during the trial. The total time spent monitoring was 365 hours, with a median (interquartile range) of 10 (7, 16) minutes per participant. An overall source to database error rate of 3.1% was found, and this did not differ between treatment groups. A low rate of error was found for all outcomes undergoing 100% source data verification, with the exception of two secondary outcomes with error rates >10%. Minimal variation in trial outcomes were found between the unmonitored and monitored datasets. Reduced degrees of source data verification and reduced cohort sizes assessed using simulated trial datasets had minimal impact on trial outcomes. CONCLUSIONS: Targeted source data verification of data critical to trial outcomes, which carried with it a substantial time investment, did not have an impact on study outcomes in this trial. This evaluation of the cost-effectiveness of targeted source data verification contributes to the evidence-base regarding the context where reduced emphasis should be placed on source data verification as the foremost monitoring activity.

A Retrospective Analysis of Hyperlipidemia and COVID-19 Outcomes Investigated in a Rural Midwestern Population.

Background COVID-19 is a respiratory disease caused by SARS-CoV-2, a coronavirus discovered in 2019. Its impact on the world continues to be studied due to the significant death toll of the disease. As the COVID-19 pandemic remains ongoing, examining the association of COVID-19 with comorbidities and resulting mortality is necessary. This study focuses on population health outcomes with COVID-19 infection and hyperlipidemia (total cholesterol greater than or equal to 200 mg/dL) as a comorbidity, including potential associations with age and sex. Methods As a retrospective analytical study, patients were divided into three populations based on COVID-19 and/or hyperlipidemia based on the International Classification of Diseases, Tenth Edition (ICD-10) codes reported in the electronic medical record system at Freeman Health System (FHS) in Southwest Missouri from April 1, 2020, to December 31, 2021. Wald's methods and two sample proportion summary hypotheses with confidence intervals (CIs) were used for comparison. The populations were subdivided and analyzed for age and sex differences. Results Patients with both COVID-19 and hyperlipidemia had a higher mortality rate than patients with COVID-19 and without hyperlipidemia and patients with hyperlipidemia and without COVID-19; patients with COVID-19 and without hyperlipidemia had a higher mortality rate than patients with hyperlipidemia and without COVID-19. All comparisons across these populations were statistically significant (p-value < 0.05). While increased age was associated with increased mortality in all groups, sex was not predictive in this regard. Conclusion Our study provides insights into variables affecting COVID-19 outcomes in a rural Midwestern population by showing how the comorbidity hyperlipidemia contributes to increased mortality.

COVID-19 and Respiratory Failure: A Retrospective Observational Study From a Rural Midwest Hospital.

Background Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) produces the coronavirus disease of 2019 (COVID-19), primarily presenting with respiratory symptoms, including cough, shortness of breath, etc. Respiratory failure can present similarly to a COVID-19 infection, and COVID-19 infection can cause respiratory failure. Thus, it is important to study respiratory failure, COVID-19, and the interaction between the two in hopes of improving patient outcomes. In this study, we compared mortality rates in patients admitted with COVID-19, respiratory failure, or both. Mortality rates in our study populations were further scrutinized based on patient age. Materials and methods Respiratory failure and COVID-19 data were collected via the electronic medical records system at Freeman Health System, a 410-bed, rural hospital, in Neosho and Joplin, Missouri, from April 2020 through December 2021. The patient population included all patients admitted to the hospital with a diagnosis of COVID-19 or respiratory failure, as defined by the International Classification of Disease, Tenth Revision (ICD-10). Patients with or without COVID-19, with or without respiratory failure, and patients with respiratory failure with COVID-19 were included. Results There was a significant increase in mortality (17.28%) in patients with COVID-19 and respiratory failure (P1) compared to patients with COVID-19 who did not have respiratory failure (P2). No significance was found when comparing patients with COVID-19 and respiratory failure (P1) and patients with respiratory failure without COVID-19 (P3) (p value=0.4921). In contrast, when divided based on age, we found a significant increase in mortality in patients 65 and older with COVID-19 and respiratory failure compared to patients 65 and older with respiratory failure who did not have COVID-19 (P5). There were no significant mortality increases in other comparisons. Conclusion When comparing patient populations within the Freeman Health System, patients with COVID-19 and respiratory failure had similar mortality rates as those with respiratory failure without COVID-19, while patients with only COVID-19 had a markedly reduced mortality rate, relatively. The higher mortality rates in patients with only respiratory failure when compared to patients with both respiratory failure and COVID-19 indicate that the presence of respiratory failure likely plays a bigger role in the inflammatory response that reduces one's chance of survival in this setting. Furthermore, age was shown to be a significant risk factor as patients aged 65 and older showed a greater mortality rate when patients had both COVID-19 and respiratory failure compared to patients with both conditions below the age of 65. The decrease in immune response that results in older patients is likely the largest contributing factor along with the increased likelihood of patients in this population also having more comorbidities, further decreasing the chance of survival. Future studies can investigate alternate treatment plans for patients aged 65 and older who are at higher risk of mortality with COVID-19 and respiratory failure.

COVID-19 and Kidney Disease (KD): A Retrospective Investigation in a Rural Southwestern Missouri Region Patient Population.

BACKGROUND: Studies have linked pre-existing kidney disease (KD) to higher rates of mortality due to coronavirus disease 2019 (COVID-19) infection. In the rural Midwest, where KD is prevalent, the impact of COVID-19 has been significant in a population that includes many patients on Medicare or Medicaid. METHODS: A retrospective cohort study was performed assessing patients with acute kidney injury (AKI), chronic kidney disease (CKD) and end stage renal disease (ESRD), with and without COVID-19. International Classification of Diseases 10th Revision codes were submitted by physicians into Freeman Health System's Electronic Medical Records and gathered from April 2020 to January 2021. The data were analyzed and compared to determine whether the mortality rate in patients with varying stages of KD and COVID-19 was higher than the mortality rate in patients with KD alone, excluding variables such as sex and age. RESULTS: The 95% confidence interval (CI) of the mortality rate of patients with COVID-19 and any degree of KD, encompassing both AKI and CKD, was between 30.21% and 37.63%. This metric was significantly higher than the 95% CI of COVID-19 infection (6.70%-9.96%, p<0.0001) or KD alone (10.89%-13.01%, p<0.0001). Within those with COVID-19 and KD, the highest rate of mortality was in patients with AKI (38.13% and 49.02%). There was not sufficient statistical support in our sample to assert that COVID-19 increased mortality in ESRD patients. CONCLUSIONS: Based on our results, patients with KD and COVID-19 are at higher risk for mortality when compared to patients with KD alone. Further studies are warranted into individual comorbidities affecting KD patient outcomes with COVID-19.

Nitric Oxide on Extracorporeal Membrane Oxygenation in Neonates and Children (NECTAR Trial): Protocol for a Randomized Controlled Trial.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) provides support for the pulmonary or cardiovascular function of children in whom the predicted mortality risk remains very high. The inevitable host inflammatory response and activation of the coagulation cascade due to the extracorporeal circuit contribute to additional morbidity and mortality in these patients. Mixing nitric oxide (NO) into the sweep gas of ECMO circuits may reduce the inflammatory and coagulation cascade activation during ECMO support. OBJECTIVE: The purpose of this study is to test the feasibility and safety of mixing NO into the sweep gas of ECMO systems and assess its effect on inflammation and coagulation system activation through a pilot randomized controlled trial. METHODS: The Nitric Oxide on Extracorporeal Membrane Oxygenation in Neonates and Children (NECTAR) trial is an open-label, parallel-group, pilot randomized controlled trial to be conducted at a single center. Fifty patients who require ECMO support will be randomly assigned to receive either NO mixed into the sweep gas of the ECMO system at 20 ppm for the duration of ECMO or standard care (no NO) in a 1:1 ratio, with stratification by support type (veno-venous vs veno-arterial ECMO). RESULTS: Outcome measures will focus on feasibility (recruitment rate and consent rate, and successful inflammatory marker measurements), the safety of the intervention (oxygenation and carbon dioxide control within defined parameters and methemoglobin levels), and proxy markers of efficacy (assessment of cytokines, chemokines, and coagulation factors to assess the impact of NO on host inflammation and coagulation cascade activation, clotting of ECMO components, including computer tomography scanning of oxygenators for clot assessments), bleeding complications, as well as total blood product use. Survival without ECMO and the length of stay in the pediatric intensive care unit (PICU) are clinically relevant efficacy outcomes. Long-term outcomes include neurodevelopmental assessments (Ages and Stages Questionnaire, Strength and Difficulties Questionnaire, and others) and quality of life (Pediatric Quality of Life Inventory and others) measured at 6 and 12 months post ECMO cannulation. Analyses will be conducted on an intention-to-treat basis. CONCLUSIONS: The NECTAR study investigates the safety and feasibility of NO as a drug intervention during extracorporeal life support and explores its efficacy. The study will investigate whether morbidity and mortality in patients treated with ECMO can be improved with NO. The intervention targets adverse outcomes in patients who are supported by ECMO and who have high expected mortality and morbidity. The study will be one of the largest randomized controlled trials performed among pediatric patients supported by ECMO. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12619001518156; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376869. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/43760.

Racial/ethnic disparities in influenza risk perception and vaccination intention among Pima County residents in Arizona.

While influenza cases in Arizona have nearly tripled since 2018, vaccination rates continue to lag. Statewide, Hispanics and African Americans had the lowest vaccination rates despite having higher influenza infection rates than Whites. Given Arizona's racial influenza vaccination disparity and the general increase in vaccination hesitancy due to COVID-19, the purpose of this study was to better understand the influences of seasonal influenza vaccination in Arizona during the COVID-19 pandemic using qualitative methods. Findings from this study revealed that many participants were motivated to get the influenza vaccine to protect their family and close friends. The heightened concern for COVID-19 prompted some Hispanic/Latino focus group discussion participants to consider getting vaccinated. However, many Hispanic/Latino participants also expressed that they stopped getting influenza vaccine due to negative vaccination experiences or concern about sickness following immunization. African American participants primarily discussed receiving the vaccine as part of their routine health visit. Compared to other races, more White participants believed that vaccination was unimportant because they were healthy, and the people they interacted with never got sick. Distinct factors influence risk perception and vaccination intention across different racial/ethnic groups. Effective interventions can account for these factors and be tailored to the target population to maximize vaccination uptake.

Effect of Nitric Oxide via Cardiopulmonary Bypass on Ventilator-Free Days in Young Children Undergoing Congenital Heart Disease Surgery: The NITRIC Randomized Clinical Trial.

Importance: In children undergoing heart surgery, nitric oxide administered into the gas flow of the cardiopulmonary bypass oxygenator may reduce postoperative low cardiac output syndrome, leading to improved recovery and shorter duration of respiratory support. It remains uncertain whether nitric oxide administered into the cardiopulmonary bypass oxygenator improves ventilator-free days (days alive and free from mechanical ventilation). Objective: To determine the effect of nitric oxide applied into the cardiopulmonary bypass oxygenator vs standard care on ventilator-free days in children undergoing surgery for congenital heart disease. Design, Setting, and Participants: Double-blind, multicenter, randomized clinical trial in 6 pediatric cardiac surgical centers in Australia, New Zealand, and the Netherlands. A total of 1371 children younger than 2 years undergoing congenital heart surgery were randomized between July 2017 and April 2021, with 28-day follow-up of the last participant completed on May 24, 2021. Interventions: Patients were assigned to receive nitric oxide at 20 ppm delivered into the cardiopulmonary bypass oxygenator (n = 679) or standard care cardiopulmonary bypass without nitric oxide (n = 685). Main Outcomes and Measures: The primary end point was the number of ventilator-free days from commencement of bypass until day 28. There were 4 secondary end points including a composite of low cardiac output syndrome, extracorporeal life support, or death; length of stay in the intensive care unit; length of stay in the hospital; and postoperative troponin levels. Results: Among 1371 patients who were randomized (mean [SD] age, 21.2 [23.5] weeks; 587 girls [42.8%]), 1364 (99.5%) completed the trial. The number of ventilator-free days did not differ significantly between the nitric oxide and standard care groups, with a median of 26.6 days (IQR, 24.4 to 27.4) vs 26.4 days (IQR, 24.0 to 27.2), respectively, for an absolute difference of -0.01 days (95% CI, -0.25 to 0.22; P = .92). A total of 22.5% of the nitric oxide group and 20.9% of the standard care group developed low cardiac output syndrome within 48 hours, needed extracorporeal support within 48 hours, or died by day 28, for an adjusted odds ratio of 1.12 (95% CI, 0.85 to 1.47). Other secondary outcomes were not significantly different between the groups. Conclusions and Relevance: In children younger than 2 years undergoing cardiopulmonary bypass surgery for congenital heart disease, the use of nitric oxide via cardiopulmonary bypass did not significantly affect the number of ventilator-free days. These findings do not support the use of nitric oxide delivered into the cardiopulmonary bypass oxygenator during heart surgery. Trial Registration: anzctr.org.au Identifier: ACTRN12617000821392.

Outcomes After Stage I Norwood Palliation in a Recently Established Program Can Achieve Results Similar to Longer Established Services.

BACKGROUND: Infants with hypoplastic left heart syndrome (HLHS) or similar single ventricle cardiac lesions require a three-stage surgical approach, the first step being the Stage I Norwood procedure. The Queensland Children's Hospital (QCH) in Australia is a tertiary hospital providing the only cardiac surgical service to children in Queensland and northern New South Wales. OBJECTIVE: To review the centre's outcomes of Norwood procedures performed in the last 6 years. MATERIALS AND METHODS: We retrospectively evaluated all infants undergoing the stage I Norwood procedure between January 2015 and August 2021. Mortality, intensive care length of stay, events of cardiac arrest following surgery and duration of mechanical ventilation were calculated and analysed for subgroups depending on type of pulmonary shunt type (right-ventricle-to-pulmonary-artery shunt [RVPAS] vs the modified Blalock-Taussig shunt [MBTS]). RESULTS: Forty-nine (49) patients were included. Overall survival to stage two operation (Glenn) was 90%. Both shunts were used evenly with the RVPA conduit preferred for HLHS and the MBTS largely chosen for hypoplastic left heart variants. In univariable analysis there was no difference in cardiac arrest or mortality rate for the patient with a RVPAS compared to the patient with a MBTS. CONCLUSION: We show that a recently established Norwood program can achieve results that are comparable to those reported by longer established centres, and the international literature.

A Retrospective Investigation: Outcome Comparisons Between Septic Patients With and Without Secondary Diagnosis of Hypothyroidism From a Rural Midwest Hospital.

Background Sepsis morbidity and mortality rates have remained high despite recent developments in clinical guidelines aimed to curtail this disease process. Understanding how sepsis interacts with comorbidities and pre-existing disease states is necessary for improving sepsis treatment. Accounting for specific pre-existing conditions in the treatment of sepsis patients may not only improve patient outcomes but also reduce healthcare costs by preventing possible complications. We sought to evaluate whether the presence of hypothyroidism affects outcomes in septic patients. Methods In this retrospective observational study, we analyzed the patient dataset from a not-for-profit rural hospital from January 2019 through June 2020. We chose the initial patient sample based on International Classification of Disease (ICD10) codes for sepsis. We then used the ICD10 code for hypothyroidism within that sample to identify the septic patients with hypothyroidism. We did two-sample proportion summary hypothesis tests to identify differences in mortality and 30-day readmission rates. Results In our dataset, we had 1,122 patients with sepsis, of whom 225 had hypothyroidism. There was no difference in sepsis outcomes between patients who had hypothyroidism compared to patients who did not have hypothyroidism. Additionally, we did not find sufficient evidence to conclude that the patient's sex affects sepsis outcomes in hypothyroid patients.  Conclusion  Within this Midwest population, the sepsis outcomes were not impacted by having hypothyroidism as a secondary diagnosis. Additionally, there was no sufficient evidence to suggest an impact on sepsis outcomes based on sex, either male or female, when considering concomitant hypothyroidism.

Research monitoring practices in critical care research: a survey of current state and attitudes.

BACKGROUND/AIMS: In 2016, international standards governing clinical research recommended that the approach to monitoring a research project should be undertaken based on risk, however it is unknown whether this approach has been adopted in Australia and New Zealand (ANZ) throughout critical care research. The aims of the project were to: 1) Gain an understanding of current research monitoring practices in academic-led clinical trials in the field of critical care research, 2) Describe the perceived barriers and enablers to undertaking research monitoring. METHODS: Electronic survey distributed to investigators, research co-ordinators and other research staff currently undertaking and supporting academic-led clinical trials in the field of critical care in ANZ. RESULTS: Of the 118 respondents, 70 were involved in the co-ordination of academic trials; the remaining results pertain to this sub-sample. Fifty-eight (83%) were working in research units associated with hospitals, 29 (41%) were experienced Research Coordinators and 19 (27%) Principal Investigators; 31 (44%) were primarily associated with paediatric research. Fifty-six (80%) develop monitoring plans with 33 (59%) of these undertaking a risk assessment; the most common barrier reported was lack of expertise. Nineteen (27%) indicated that centralised monitoring was used, noting that technology to support centralised monitoring (45/51; 88%) along with support from data managers and statisticians (45/52; 87%) were key enablers. Coronavirus disease-19 (COVID-19) impacted monitoring for 82% (45/55) by increasing remote (25/45; 56%) and reducing onsite (29/45; 64%) monitoring. CONCLUSIONS: Contrary to Good Clinical Practice guidance, risk assessments to inform monitoring plans are not being consistently performed due to lack of experience and guidance. There is an urgent need to enhance risk assessment methodologies and develop technological solutions for centralised statistical monitoring.

Compliance with SEP-1 guidelines is associated with improved outcomes for septic shock but not for severe sepsis.

Background: In 2018, the Centers for Medicaid and Medicare Services (CMS) issued a protocol for the treatment of sepsis. This bundle protocol, titled SEP-1 is a multicomponent 3 h and 6 h resuscitation treatment for patients with the diagnosis of either severe sepsis or septic shock. The SEP-1 bundle includes antibiotic administration, fluid bolus, blood cultures, lactate measurement, vasopressors for fluid-refractory hypotension, and a reevaluation of volume status. We performed a retrospective analysis of patients diagnosed with either severe sepsis or septic shock comparing mortality outcomes based on compliance with the updated SEP-1 bundle at a rural community hospital. Methods: Mortality outcome and readmission data were extracted from an electronic medical records database from January 1, 2019, to June 30, 2020. International Classification of Diseases (ICD)-10 codes were used to identify patients with either severe sepsis or septic shock. Once identified, patients were separated into four populations: patients with severe sepsis who met SEP-1, patients with severe sepsis who failed SEP-1, patients with septic shock who met SEP-1, and patients with septic shock who failed SEP-1. A patient who met bundle criteria (SEP-1 criteria) received each component of the bundle in the time allotted. Using chi-squared test of homogeneity, mortality outcomes for population proportions were investigated. Two sample proportion summary hypothesis test and 95% confidence intervals (CI) determined significance in mortality outcomes. Results: Out of our 1122 patient population, 437 patients qualified to be measured by CMS criteria. Of the 437 patients, 195 met the treatment bundle and 242 failed the treatment bundle. Upon comparing the two groups, we found the probable difference in mortality rate between the met(14.87%) and failed bundle(27.69%) groups to be significant(95% CI: 5.28-20.34, P=0.0013). However, the driving force of this result lies in the subgroup of patients with severe sepsis with septic shock, which show a higher mortality rate compared to the subgroup with just severe sepsis. The difference was within the range of 3.31% to 29.71%. Conclusion: This study shows that with septic shock obtained a benefit, decreased mortality, when the SEP-1 bundle was met. However, meeting the SEP-1 bundle had no benefit for patients who had the diagnosis of severe sepsis alone. The significant difference in mortality, found between the met and failed bundle groups, is primarily due to the number of patients with septic shock, and whether or not those patients with septic shock met or failed the bundle.

Merging Two Hospitals: The Effects on Pediatric Extracorporeal Cardiopulmonary Resuscitation Outcomes.

In this article, a retrospective study was performed to describe the impact of merging two pediatric intensive care units on the overall and neurocognitive outcomes of children who required extracorporeal cardiopulmonary resuscitation (ECPR). Results from three cohorts were compared: 2008 to 2014: premerge, 2014 to 2017: initial time period postmerge, and 2018 to 2019: established merge. Survival to hospital discharge (and with good neurological outcome) was of 68% (61%), 46% (36%), and 79% (71%), respectively, for the three time periods. Merging two hospitals resulted in a nonsignificant trend toward temporary worse outcomes in pediatric patients requiring ECPR.

Pediatric Thromboelastograph 6s and Laboratory Coagulation Reference Values.

CONTEXT.­: Specific reference intervals (RIs) facilitate accurate interpretation of results. Coagulation assay results may vary by demographics and also between reagents and analyzers used. Current Thromboelastograph 6s (TEG 6s) Hemostasis Analyzer RIs were generated from adult samples. OBJECTIVE.­: To generate reagent analyzer-specific pediatric RIs for TEG 6s and coagulation parameters. DESIGN.­: A prospective, observational, single-center study of healthy children undergoing general anesthesia (January 3, 2017 to January 3, 2019). Venous blood samples were obtained for TEG 6s (Kaolin, Kaolin-Heparinase, Rapid and Functional Fibrinogen assays) and coagulation parameters (activated partial thromboplastin time, prothrombin time, thrombin clotting time, Echis time, antithrombin activity, and fibrinogen concentration using Instrumentation Laboratory ACL-TOP analyzers). Differences between activated partial thromboplastin time and prothrombin time reagents were investigated using mixed-effects regression, comparing maximum coefficients-of-variation with assay-specific allowable variation. RIs (lower/upper limits 2.5th of 97.5th percentiles) were generated using the following 2 methods: within discrete age-groups (neonates [<1 month], infants [1 month-1 year], young children [1-5 years], older children [6-10 years], and adolescents [11-16 years]), and modeled as functions of age and/or sex using quantile regression, including significant fractional polynomial and interaction terms. RESULTS.­: Variation between prothrombin time and activated partial thromboplastin time assays using different reagents was clinically significant. Reagent-analyzer specific pediatric RIs were generated using data from 254 children. Discrete and model-based RIs varied by age for all coagulation parameters and TEG 6s variables in all assays. CONCLUSIONS.­: We report reagent-analyzer specific pediatric RIs for TEG 6s and coagulation parameters. Observed variation reinforces recommendations for laboratory-specific RIs. These findings improve accuracy of interpretation of clinical results, provide a foundation for comparison and validation of tests in pathology, and illustrate feasibility and advantages of model-based RI approaches.

Statistical analysis plan for the NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC) trial.

Background: The NITric oxide during cardiopulmonary bypass (CPB) to improve Recovery in Infants with Congenital heart defects (NITRIC) trial, a 1320-patient, multicentre, randomised controlled trial, is aiming to improve survival free of ventilation after CPB by using nitric oxide delivered into the oxygenator of the CPB. Objective: To provide a statistical analysis plan before completion of patient recruitment and data monitoring. Final analyses for this study will adhere to this statistical analysis plan, which details all key pre-planned analyses. Stata scripts for analyses have been prepared alongside this statistical analysis plan. Methods: The statistical analysis plan was designed collaboratively by the chief investigators and trial statistician and builds on the previously published study protocol. All authors remain blinded to treatment allocation. Detail is provided on statistical analyses including cohort description, analysis of primary and secondary outcomes and adverse events. Statistical methods to compare outcomes are planned in detail to ensure methods are verifiable and reproducible. Results: The statistical analysis plan developed provides the trial outline, list of mock tables, and analysis scripts. The plan describes statistical analyses on cohort and baseline description, primary and secondary outcome analyses, process of care measures, physiological descriptors, and safety and adverse event reporting. We define the pre-specified subgroup analyses and the respective statistical tests used to compare subgroups. Conclusion: The statistical analysis plan for the NITRIC trial establishes detailed pre-planned analyses alongside Stata scripts to analyse the largest trial in the field of neonatal and paediatric heart surgery. The plan ensures standards for trial analysis validity aiming to minimise bias of analyses. Trial registration: ACTRN12617000821392.

Antithrombin Dosing Guidelines in Children Underestimate Dose Needed for Plasma Level Increase.

OBJECTIVES: Antithrombin is a cofactor in the coagulation cascade with mild anticoagulant activity and facilitates the action of heparin as an anticoagulant. Antithrombin concentrate dosing guidelines vary but most commonly suggest that each unit of antithrombin concentrate per body weight increases the plasma antithrombin level by 1.5% to 2.2% (depending on manufacturer). We aimed to establish a dosing recommendation dependent on age and disease state. DESIGN: A retrospective analysis of all antithrombin concentrate doses over a period of 5 years. We calculated the increase any respective antithrombin concentrate dose achieved, indexed by body weight, and performed a multivariable analysis to establish independent factors associated with the effectiveness of antithrombin concentrate. SETTING: A PICU at a university-affiliated children's hospital. PATIENTS: One hundred fifty-five patients treated in a PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The effect of 562 doses of antithrombin concentrate on plasma antithrombin levels administered to 155 patients, of which 414 (73.7%) antithrombin concentrate doses administered during extracorporeal life support treatment, were analyzed. For all patients, each unit of antithrombin concentrate/kg increased plasma antithrombin level by 0.86% (SD 0.47%). Plasma antithrombin level increase was influenced by body weight (increase of 0.76% [interquartile range, 0.6-0.92%] for patients < 5 kg; 1.38% [interquartile range, 1.11-2.10%] for > 20 kg), disease state (liver failure having the poorest antithrombin increase) and whether patients were treated with extracorporeal circulatory support (less antithrombin increase on extracorporeal life support). Heparin dose at the time of administration did not influence with amount of change in antithrombin level. CONCLUSIONS: Current antithrombin concentrate dosing guidelines overestimate the effect on plasma antithrombin level in critically ill children. Current recommendations result in under-dosing of antithrombin concentrate administration. Age, disease state, and extracorporeal life support should be taken into consideration when administering antithrombin concentrate.

Racial disparities in breast cancer hereditary risk assessment referrals.

For poorly understood reasons, Black non-Hispanic (BNH) women meeting National Comprehensive Cancer Network (NCCN) criteria for genetic testing for breast cancer risk are less likely than White non-Hispanic (WNH) women to undergo testing (Armstrong, Micco, Carney, Stopfer, & Putt, JAMA, 293, 1729 and 2005). We compared physician referral rates and uptake for genetic testing of BNH and WNH women meeting select NCCN criteria (breast cancer under age 50, two primary breast cancers, triple-negative disease under age 60) in the Cancer Center at George Washington University (GWCC) between 2015 and 2018. Of the 723 BNH and WNH patients treated for breast cancer at GWCC, 28% met study criteria for genetic counseling referral (n = 252; BNH n = 115, WNH n = 137). Physician referral rates to genetic counseling differed significantly by race (BNH 75.7%, n = 87 and WNH 92.7%; n = 127; χ2  = 14.19, p-value < .01). Once referred, though, there was no significant difference in uptake of genetic counseling by race (BNH 95.4%, n = 83; WNH 97.6%, n = 124, χ2  = 1.33, p-value = .25) for patients appropriately referred.

Study protocol: NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC trial): a randomised controlled trial.

INTRODUCTION: Congenital heart disease (CHD) is a major cause of infant mortality. Many infants with CHD require corrective surgery with most operations requiring cardiopulmonary bypass (CPB). CPB triggers a systemic inflammatory response which is associated with low cardiac output syndrome (LCOS), postoperative morbidity and mortality. Delivery of nitric oxide (NO) into CPB circuits can provide myocardial protection and reduce bypass-induced inflammation, leading to less LCOS and improved recovery. We hypothesised that using NO during CPB increases ventilator-free days (VFD) (the number of days patients spend alive and free from invasive mechanical ventilation up until day 28) compared with standard care. Here, we describe the NITRIC trial protocol. METHODS AND ANALYSIS: The NITRIC trial is a randomised, double-blind, controlled, parallel-group, two-sided superiority trial to be conducted in six paediatric cardiac surgical centres. One thousand three-hundred and twenty infants <2 years of age undergoing cardiac surgery with CPB will be randomly assigned to NO at 20 ppm administered into the CPB oxygenator for the duration of CPB or standard care (no NO) in a 1:1 ratio with stratification by age (<6 and ≥6 weeks), single ventricle physiology (Y/N) and study centre. The primary outcome will be VFD to day 28. Secondary outcomes include a composite of LCOS, need for extracorporeal membrane oxygenation or death within 28 days of surgery; length of stay in intensive care and in hospital; and, healthcare costs. Analyses will be conducted on an intention-to-treat basis. Preplanned secondary analyses will investigate the impact of NO on host inflammatory profiles postsurgery. ETHICS AND DISSEMINATION: The study has ethical approval (HREC/17/QRCH/43, dated 26 April 2017), is registered in the Australian New Zealand Clinical Trials Registry (ACTRN12617000821392) and commenced recruitment in July 2017. The primary manuscript will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ACTRN12617000821392.

Coagulation monitoring correlation with heparin dose in pediatric extracorporeal life support.

OBJECTIVES: Extracorporeal Life Support (ECLS) risks thrombotic and hemorrhagic complications. Optimal anti-coagulation monitoring is controversial. We compared coagulation tests evaluating the heparin effect in pediatric ECLS. METHODS: A retrospective study of children (<18yrs) undergoing ECLS over 12 months in a tertiary pediatric intensive care unit (PICU). Variables included anti-Factor Xa activity (anti-Xa), activated partial thromboplastin time (aPTT), activated clotting time (ACT) and thromboelastogram (TEG®6s) parameters: ratio and delta reaction (R) times (the ratio and difference, respectively, between R times in kaolin assays with and without heparinase). Test results were correlated with unfractionated heparin infusion rate (IU/kg/hr) at the time of sampling. Mean test results of each ECLS run were evaluated according to the presence/absence of complications. RESULTS: Thirty-two ECLS runs (31 patients) generated 695 data-points for correlation. PICU mortality was 22% and the thrombotic complication rate was 66%. The proportion of variation in coagulation test results explained by heparin dose was 13.3% for anti-Xa, 11.9% for ratio R time, and 9.9% for delta R time, compared with <1% for ACT and aPTT. Incorporating individual variation, age and antithrombin activity in a model with heparin dose explained less than 50% of the variation in test results. Correlation varied according to age, day of ECLS run and between individuals, with parallel dose-response lines noted between patients. Significantly lower mean anti-Xa was observed in PICU non-survivors and runs with thrombosis. CONCLUSION: Lower anti-Xa was observed in ECLS runs with complications. Although absolute results from anti-Xa and TEG6®s showed the best correlation with heparin dose, a large proportion of variation in results was unexplained by heparin, while dose response was similar between individuals. Population pharmacokinetic/pharmacodynamic modelling is required, as well as prospective trials to delineate the superior means of adjusting heparin therapy to prevent adverse clinical outcomes.