Intensive Care Unit-free Days Research Articles

An open-label, randomized controlled trial to assess a ketogenic diet in critically ill patients with sepsis.

Patients with sepsis experience metabolic and immunologic dysfunction that may be amplified by standard carbohydrate-based nutrition. A ketogenic diet (KD) may offer an immunologically advantageous alternative, although clinical evidence is limited. We conducted a single-center, open-label, randomized controlled trial to assess whether a KD could induce stable ketosis in critically ill patients with sepsis. Secondary outcomes included assessment of feasibility and safety of KD, as well as explorative analysis of clinical and immunological characteristics. Forty critically ill adults were randomized to either a ketogenic or standard high-carbohydrate diet. Stable ketosis was achieved in all KD patients, with significant increases in β-hydroxybutyrate levels compared with controls [mean difference 1.4 milimoles per liter; 95% confidence interval (CI): 1.0 to 1.8; P < 0.001). No major adverse events or harmful metabolic side effects (acidosis, dysglycemia, or dyslipidemia) were observed. After day 4, none of the patients in the KD group required insulin treatment, whereas in the control group, insulin dependency ranged between 35% and 60% (P = 0.009). There were no differences in 30-day survival, but ventilation-free [incidence rate ratio (IRR) 1.7; 95% CI: 1.5 to 2.1; P < 0.001], vasopressor-free (IRR 1.7; 95% CI: 1.5 to 2.0; P < 0.001), dialysis-free (IRR 1.5; 95% CI: 1.3 to 1.8; P < 0.001), and intensive care unit-free days (IRR 1.7; 95% CI: 1.4 to 2.1; P < 0.001) were higher in the ketogenic group. Next-generation sequencing of CD4+/CD8+ T cells and protein analyses showed reduced immune dysregulation, with decreased gene expression of T-cell activation and signaling markers and lower pro-inflammatory cytokine secretion. This trial demonstrated the safe induction of a stable ketogenic state in sepsis, warranting larger trials to investigate potential benefits in sepsis-related organ dysfunction.

An open-label, randomized controlled trial to assess a ketogenic diet in critically ill patients with sepsis.

Patients with sepsis experience metabolic and immunologic dysfunction that may be amplified by standard carbohydrate-based nutrition. A ketogenic diet (KD) may offer an immunologically advantageous alternative, although clinical evidence is limited. We conducted a single-center, open-label, randomized controlled trial to assess whether a KD could induce stable ketosis in critically ill patients with sepsis. Secondary outcomes included assessment of feasibility and safety of KD, as well as explorative analysis of clinical and immunological characteristics. Forty critically ill adults were randomized to either a ketogenic or standard high-carbohydrate diet. Stable ketosis was achieved in all KD patients, with significant increases in β-hydroxybutyrate levels compared with controls [mean difference 1.4 milimoles per liter; 95% confidence interval (CI): 1.0 to 1.8; P < 0.001). No major adverse events or harmful metabolic side effects (acidosis, dysglycemia, or dyslipidemia) were observed. After day 4, none of the patients in the KD group required insulin treatment, whereas in the control group, insulin dependency ranged between 35% and 60% (P = 0.009). There were no differences in 30-day survival, but ventilation-free [incidence rate ratio (IRR) 1.7; 95% CI: 1.5 to 2.1; P < 0.001], vasopressor-free (IRR 1.7; 95% CI: 1.5 to 2.0; P < 0.001), dialysis-free (IRR 1.5; 95% CI: 1.3 to 1.8; P < 0.001), and intensive care unit-free days (IRR 1.7; 95% CI: 1.4 to 2.1; P < 0.001) were higher in the ketogenic group. Next-generation sequencing of CD4+/CD8+ T cells and protein analyses showed reduced immune dysregulation, with decreased gene expression of T-cell activation and signaling markers and lower pro-inflammatory cytokine secretion. This trial demonstrated the safe induction of a stable ketogenic state in sepsis, warranting larger trials to investigate potential benefits in sepsis-related organ dysfunction.

Hydrocortisone plus fludrocortisone for community acquired pneumonia-related septic shock: a subgroup analysis of the APROCCHSS phase 3 randomised trial

Glucocorticoids probably improve outcomes in patients hospitalised for community acquired pneumonia (CAP). In this a priori planned exploratory subgroup analysis of the phase 3 randomised controlled Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial, we aimed to investigate responses to hydrocortisone plus fludrocortisone between CAP and non-CAP related septic shock. APROCCHSS was a randomised controlled trial that investigated the effects of hydrocortisone plus fludrocortisone, drotrecogin-alfa (activated), or both on mortality in septic shock in a two-by-two factorial design; after drotrecogin-alfa was withdrawn on October 2011, from the market, the trial continued on two parallel groups. It was conducted in 34 centres in France. In this subgroup study, patients with CAP were a preselected subgroup for an exploratory secondary analysis of the APROCCHSS trial of hydrocortisone plus fludrocortisone in septic shock. Adults with septic shock were randomised 1:1 to receive, in a double-blind manner, a 7-day treatment with daily administration of intravenous hydrocortisone 50 mg bolus every 6h and a tablet of 50 μg of fludrocortisone via the nasogastric tube, or their placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included all-cause mortality at intensive care unit (ICU) and hospital discharge, 28-day and 180-day mortality, the number of days alive and free of vasopressors, mechanical ventilation, or organ failure, and ICU and hospital free-days to 90-days. Analysis was done in the intention-to-treat population. The trial was registered at ClinicalTrials.gov (NCT00625209). Of 1241 patients included in the APROCCHSS trial, CAP could not be ruled in or out in 31 patients, 562 had a diagnosis of CAP (279 in the placebo group and 283 in the corticosteroid group), and 648 patients did not have CAP (329 in the placebo group and 319 in the corticosteroid group). In patients with CAP, there were 109 (39%) deaths of 283 patients at day 90 with hydrocortisone plus fludrocortisone and 143 (51%) of 279 patients receiving placebo (odds ratio [OR] 0·60, 95% CI 0·43-0·83). In patients without CAP, there were 148 (46%) deaths of 319 patients at day 90 in the hydrocortisone and fludrocortisone group and 157 (48%) of 329 patients in the placebo group (OR 0·95, 95% CI 0·70-1·29). There was significant heterogeneity in corticosteroid effects on 90-day mortality across subgroups with CAP and without CAP (p=0·046 for both multiplicative and additive interaction tests; moderate credibility). Of 1241 patients included in the APROCCHSS trial, 648 (52%) had ARDS (328 in the placebo group and 320 in the corticosteroid group). There were 155 (48%) deaths of 320 patients at day 90 in the corticosteroid group and 186 (57%) of 328 patients in the placebo group. The OR for death at day 90 was 0·72 (95% CI 0·53-0·98) in patients with ARDS and 0·85 (0·61-1·20) in patients without ARDS (p=0·45 for multiplicative interaction and p=0·42 for additive interaction). The OR for observing at least one serious adverse event (corticosteroid group vs placebo) within 180 days post randomisation was 0·64 (95% CI 0·46-0·89) in the CAP subgroup and 1·02 (0·75-1·39) in the non-CAP subgroup (p=0·044 for multiplicative interaction and p=0·042 for additive interaction). In a pre-specified subgroup analysis of the APROCCHSS trial of patients with CAP and septic shock, hydrocortisone plus fludrocortisone reduced mortality as compared with placebo. Although a large proportion of patients with CAP also met criteria for ARDS, the subgroup analysis was underpowered to fully discriminate between ARDS and CAP modifying effects on mortality reduction with corticosteroids. There was no evidence of a significant treatment effect of corticosteroids in the non-CAP subgroup. Programme Hospitalier de Recherche Clinique of the French Ministry of Health, by Programme d'Investissements d'Avenir, France 2030, and IAHU-ANR-0004.

High dose esomeprazole as an anti-inflammatory agent in sepsis: Protocol for a randomized controlled trial

BackgroundSepsis is caused by dysregulated immune responses due to infection and still presents high mortality rate and limited efficacious therapies, apart from antibiotics. Recent evidence suggests that very high dose proton pump inhibitors might regulate major sepsis mediators' secretion by monocytes, which might attenuate excessive host reactions and improve clinical outcomes. This effect is obtained with doses which are approximately 50 times higher than prophylactic esomeprazole single daily administration and 17 times higher than the cumulative dose of a three day prophylaxis. We aim to perform a randomized trial to investigate if high dose esomeprazole reduces organ dysfunction in patients with sepsis or septic shock. MethodsThis study, called PPI-SEPSIS, is a multicenter, randomized, double blind, placebo-controlled clinical trial on critically ill septic patients admitted to the emergency department or intensive care unit. A total of 300 patients will be randomized to receive high dose esomeprazole (80 mg bolus followed by 12 mg/h for 72 h and a second 80 mg bolus 12 h after the first one) or equivolume placebo (sodium chloride 0.9%), with 1:1 allocation. The primary endpoint of the study will be mean daily Sequential Organ Failure Assessment (SOFA) score over 10 days. Secondary outcomes will include antibiotic-free days, single organ failure severity, intensive care unit-free days at day 28, and mortality. DiscussionThis trial aims to test the efficacy of high dose esomeprazole to reduce acute organ dysfunction in patients with septic shock.Trial registration: This trial was registered on ClinicalTrials.gov with the trial identification NCT03452865 in March 2018.

Low-dose versus high-dose dexamethasone for hospitalized patients with COVID-19 pneumonia: A randomized clinical trial.

BackgroundDexamethasone 6 mg daily for 10 days is the recommended treatment for patients with severe or critical coronavirus disease 2019 (COVID-19). The evidence on the benefit of high-dose dexamethasone is limited. The goal of this study was to assess the effects of 6 mg daily vs. 20 mg daily of dexamethasone in hospitalized patients with COVID-19 pneumonia.MethodsWe conducted a single-center, randomized, clinical trial involving hospitalized patients with COVID-19 pneumonia. Participants were randomized 1:1 to dexamethasone 6 mg daily or dexamethasone 20 mg daily, and were stratified by the WHO-Ordinal Scale for Clinical Improvement (OSCI). The primary outcome was clinical improvement equal to or greater than 2 points by OSCI on day 28. Secondary outcomes were 28-day mortality, intensive care unit-free days, and ventilator-free days on day 28.ResultsOf the 107 patients who enrolled and completed the follow up, 55 patients enrolled in the low-dose group and 52 patients enrolled in the high-dose group. Treatment with dexamethasone 20 mg daily compared with dexamethasone 6 mg daily did not result in better clinical improvement based on OSCI on day 28 (71.2% vs. 78.2%; odds ratio, 1.45 [0.55–3.86]; p = 0.403). For participants who required high-flow oxygen or noninvasive ventilation at randomization, the 6-mg group had better survival than the 20-mg group on day 28 (100% vs. 57.1%; p = 0.025). Although more participants in the 6-mg group received immune modulators (40% vs. 21.2%; p = 0.035), 50% of death cases in the 20-mg group who required high-flow oxygen or noninvasive ventilation at randomization received immune modulators.ConclusionsDexamethasone 20 mg daily did not result in better clinical outcome improvement, and was probably associated with higher 28-day mortality in patients on high-flow oxygen or noninvasive ventilation, compared with dexamethasone 6 mg daily.Trial registrationClinialtrials.gov number, NCT04707534, registered January 13, 2021

The Ventilatory Equivalent for Carbon Dioxide Slope Independently Predicts Perioperative Outcomes in Patients Undergoing Heart Transplantation

<h3>Purpose</h3> Cardiopulmonary exercise test (CPET) is commonly used to evaluate patients for heart transplantation (HTX), with the focus being on peak oxygen uptake (VO2). Although the ventilatory equivalent for carbon dioxide (VE/VCO2) slope during exercise predicts survival in patients with advanced heart failure, it has not been shown to predict outcomes from heart transplantation. We aimed to assess its utility in predicting perioperative outcomes following heart transplantation. <h3>Methods</h3> We retrospectively reviewed all patients who underwent CPET within 18 months prior to HTX between January 2002 and August 2021 at our centre. VE/VCO2 slope and peak oxygen consumption (VO2) for each patient was measured and evaluated with recipient and transplant characteristics. The primary outcome was days alive and free of the intensive care unit (ICU) within 30 days of HTX, and the secondary outcome was a composite outcome of postoperative morbidity (defined as either one of respiratory failure, primary graft failure, stroke, bloodstream infection, renal failure, ICU readmission, or mortality). We used a Pearson correlation coefficient and Mann-Whitney U test to respectively assess the association of the continuous variable of VE/VCO2 slope and VE/VCO2slope >35 with ICU-Free days. Multiple regression of VE/VCO2 slope >35 in conjunction with other transplant characteristics was used to assess if VE/VCO2 slope independently predicts ICU-Free days and postoperative morbidity. <h3>Results</h3> 61 patients met the inclusion criteria. There was a correlation between VE/VCO2 slope and ICU free days (R= -.264; p=0.04). VE/VCO2 slope >35 was associated with significantly lower median ICU-free days (23 vs 26.5 days; p<0.01) and a higher odds of postoperative morbidity (OR=5.64, 95% CI=1.75-18.16; p<0.01). Multiple regression analysis showed VE/VCO2 slope >35 is independently associated with lower ICU-free days (p<0.01) and postoperative morbidity (p=0.02) when controlled for age, sex, ethnicity, diagnosis, peak VO2, cardiac index, PVR, and creatinine. No other factor independently predicted ICU-free days or postoperative mortality. <h3>Conclusion</h3> VE/VCO2 slope >35 is independently associated with lower postoperative morbidity following HTX even after controlling for peak VO2 and right heart catheter parameters.

Tranexamic acid is not inferior to placebo with respect to adverse events in suspected traumatic brain injury patients not in shock with a normal head computed tomography scan: A retrospective study of a randomized trial.

A 2-g bolus of tranexamic acid (TXA) has been shown to reduce 28-day mortality in a randomized controlled trial. This study investigates whether out-of-hospital TXA use is associated with adverse events or unfavorable outcomes in suspected traumatic brain injury (TBI) when intracranial hemorrhage (ICH) is absent on initial computed tomography. This study used data from a 2015 to 2017, multicenter, randomized trial studying the effect of the following TXA doses on moderate to severe TBI: 2-g bolus, 1-g bolus plus 1-g infusion over 8 hours, and a placebo bolus with placebo infusion. Of the 966 participants enrolled, 395 with an initial computed tomography negative for ICH were included in this analysis. Fifteen adverse events (28-day incidence) were studied: myocardial infarction, deep vein thrombosis, seizure, pulmonary embolism, acute respiratory distress syndrome, cardiac failure, liver failure, renal failure, cerebrovascular accident, cardiac arrest, cerebral vasospasm, "any thromboembolism," hypernatremia, acute kidney injury, and infection. Other unfavorable outcomes analyzed include mortality at 28 days and 6 months, Glasgow Outcome Scale-Extended score of ≤4 at discharge and 6 months, intensive care unit-free days, ventilator-free days, hospital-free days, and combined unfavorable outcomes. In both study drug groups, the incidence of dichotomous outcomes and quantity of ordinal outcomes were compared with placebo. No statistically significant increase in adverse events or unfavorable outcomes was found between either TXA dosing regimen and placebo. Demographics and injury scores were not statistically different other than two methods of injury, which were overrepresented in the 1-g TXA bolus plus 1-g TXA infusion. Administration of either a 2-g TXA bolus or a 1-g TXA bolus plus 1-g TXA 8-hour infusion in suspected TBIs without ICH is not associated with increased adverse events or unfavorable outcomes. Because the out-of-hospital 2-g bolus is associated with a mortality benefit, it should be administered in suspected TBI. Therapeutic/Care Management; Level II.

Midterm Outcomes of Heart Transplantation in Children With Genetic Disorders

BackgroundMany congenital heart diseases (CHD) are associated with genetic defects. Children with complex CHD often have heart failure requiring heart transplant. Given the broad spectrum of genetic pathologies and dearth of transplants performed in these children, little is known regarding their outcomes. MethodsWe conducted a retrospective review of heart transplants performed at a high-volume center from 2007 to 2021. Patients were separated into pathogenic molecular and copy number variants, aneuploidies, and variants of uncertain significance, and compared with patients without known genetic diagnoses. Variables included genetic diagnoses, bridge-to-transplant approach, preoperative comorbidities, operative characteristics, and postoperative complications. Outcomes included intensive care unit-free days to 28 days, hospital mortality, survival, rejection, retransplantation, and educational status at latest follow-up. ResultsIn all, 223 patients received transplants over the study period: 9.9% (22 of 223) had pathogenic molecular variants; 4.5% (10 of 223) had copy number variants; 1.8% (4 of 223) had aneuploidies; and 9% (20 of 223) had variants of uncertain significance. The most common anomalies were Turner syndrome (n = 3) and 22q11.2 deletion syndrome (n = 2). Children with aneuploidies had higher rates of hepatic dysfunction and hypothyroidism, whereas children with pathogenic copy number variants had higher rates of preoperative gastrostomy and stroke. Children with aneuploidies were intubated longer after transplant, with greater need for reintubation, and had the fewest intensive care unit-free days. Mortality and mean survival did not differ. At median follow-up of 4.4 years (range, 1.9 to 8.8), 89.7% of survivors (26 of 29) with pathogenic anomalies were attending or had graduated school. ConclusionsDespite more preoperative comorbidities, midterm outcomes after heart transplant in children with genetic syndromes and disorders are promising.

Abstract 10874: Evaluation of Intensive Care Unit and Ventilator-free Days as Alternative Outcomes in Out-of-Hospital Cardiac Arrest Trials

Objective: Compared with traditional out-of-hospital cardiac arrest (OHCA) trial outcomes such as hospital survival, alternative outcomes such as intensive care unit-free (IFD) and ventilator-free days (VFD) have potential advantages including requiring smaller sample sizes to detect significant differences. Few studies have evaluated these outcomes in OHCA. We sought to evaluate the utility and validity of IFD and VFD as candidate outcomes for OHCA trials. Methods: We analyzed data from the Pragmatic Airway Resuscitation Trial (PART), which tested laryngeal tube (LT) vs. endotracheal intubation (ETI) airway strategies in adult OHCA. We defined IFD as the number of days alive and permanently out of ICU during the first 30 days after the OHCA event. We examined IFD distribution and correlation with Modified Rankin Scale (MRS). To test associations with trial interventions, we applied a range of analytic strategies, including modeling IFD as continuous (Generalized Estimating Equations - GEE), non-parametric (Wilcoxon Rank-Sum test - WRS) and count (zero-inflated negative binomial regression - ZINB) data. We also modeled time-to-ICU discharge using a survival model with death as a competing risk. We repeated the analysis assessing VFD. Results: IFD was available for 2,898 of 3,004 patients. IFD was skewed and J-shaped; 91% IFD=0 and 5.3% IFD≥22. Mean (±SD) IFD was 2.0±6.6 days; 21.2±7.5 days for survivors. IFD varied by intervention (LT 2.4±7.2, ETI 1.6±5.8 days). IFD and VFD strongly correlated with MRS (ρ= -0.88, -0.89). LT was associated with increased IFD using GEE, WRS, and ZINB, but not competing risks model. (Table) LT was associated with increased VFD using GEE and WRS, but not ZINB or competing risks models. Conclusion: IFD and VFD differentiated OHCA interventions, suggesting their utility. IFD and VFD were highly correlated with MRS, suggesting validity. IFD and VFD have important features that may influence OHCA trial design.

Immunomodulator use in paediatric severe sepsis and septic shock

The use of drugs that modulate the immune system during paediatric severe sepsis and septic shock may alter the course of disease and is poorly studied. This study aims to characterise these children who received immunomodulators and describe their clinical outcomes. This is a retrospective chart review of patients with severe sepsis and septic shock admitted into the paediatric intensive care unit (PICU). Clinical, haematological and outcome characteristics of patients with or without exposure to immune-modulating drugs were compared. Primary outcome was PICU mortality; secondary outcomes were 28-day ventilator-free days (VFD) and intensive care unit-free days (IFD). Univariate and multivariable analyses were performed for these outcomes. A total of 109 patients with paediatric severe sepsis or septic shock were identified. Of this number, 47 (43.1%), 16 (14.7%) and 3 (2.8%) patients received systemic corticosteroids, intravenous immunoglobulins and granulocyte colony stimulating factor, respectively. Patients who received immune-modulating drugs were more likely to require invasive ventilation (38/54 [70.4%] versus 26/55 [47.3%], P=0.019) compared to those who did not. PICU mortality was indifferent between the 2 groups (20/54 [37.0%] vs 11/55 [20.0%], P=0.058) even after accounting for chronic complex conditions and admission organ dysfunction (PELOD score) (adjusted odds ratio 1.90, confidence interval [0.72-5.01], P=0.193). However, VFD (19.5 [0-28] vs 25 [12-28] days, P=0.038) and IFD (15 [0-24] vs 22 [9-26] days, P=0.024) were decreased in the immunomodulator group compared to the non-immunomodulator group. Immune-modulating drugs were frequently used in paediatric severe sepsis and septic shock. Patients who received these drugs seemed to require more PICU support. Further studies are required to examine this association thoroughly.

Fluid overload in children with pediatric acute respiratory distress syndrome: A retrospective cohort study.

To assess the association of cumulative fluid overload (FO) up to 14 days from the diagnosis of pediatric acute respiratory syndrome (PARDS) with pediatric intensive care unit (PICU) mortality, 28-day mechanical ventilation free days (VFD), and 28-day intensive care unit free days (IFD). We hypothesized that fluid overload, even beyond the acute period, would be associated with increased morbidity and mortality. We conducted a retrospective cohort study of PARDS patients admitted to PICU from 2009 to 2015. For repeated admissions, we considered the admission with the highest oxygenation index (OI). Daily FO (%) was calculated as (intake - output)/weight at PICU admission × 100. Peak cumulative FO (CFO) was the highest CFO from the diagnosis of PARDS to Day 14 or to PICU discharge or mortality, whichever was earliest. Rate to peak CFO was the peak CFO divided by the number of days to reach that highest CFO. The association of FO with mortality, VFD and IFD were analyzed with logistic and linear regression models, with the following covariates: Pediatric Index of Mortality 2 score, PARDS severity, and the presence of acute kidney injury (AKI). There were 165 patients included in this study, with a mortality rate of 45.5% (75/165), median age 3.2 years (interquartile range [IQR] 0.7-9.9) and OI 15.8 (IQR 9.5-27.9). Seventy-three (44.2%) patients had severe PARDS and 64 (38.8%) had AKI. AKI (aOR [adjusted odds ratio] 3.19, 95% CI [confidence interval] 1.43-7.09, p = 0.004) and rate to peak cumulative FO (aOR 1.23, 95% CI 1.07-1.42, p = 0.004) were associated with mortality. AKI and peak cumulative FO were associated with decreased VFD and IFD. The rate to peak CFO over the first 14 days of PARDS was associated with mortality and peak CFO was associated with decreased VFD and IFD.

Four-factor prothrombin complex concentrate to reduce allogenic blood product transfusion in patients with major trauma, the PROCOAG trial: study protocol for a randomized multicenter double-blind superiority study

BackgroundOptimal management of severe trauma patients with active hemorrhage relies on adequate initial resuscitation. Early administration of coagulation factors improves post-traumatic coagulation disorders, and four-factor prothrombin complex concentrate (PCC) might be useful in this context. Our main hypothesis is that four-factor PCC in addition to a massive transfusion protocol decreases blood product consumption at day 1 in severe trauma patients with major bleeding.MethodsThis is a prospective, randomized, multicenter, double-blind, parallel, controlled superiority trial. Eligible patients are trauma patients with major bleeding admitted to a French level-I trauma center. Patients randomized in the treatment arm receive 1 mL/kg (25 IU/ml of Factor IX/Kg) four-factor PCC within 1-h post-admission while patients randomized in the controlled group receive 1 mL/kg of saline solution 0.9% as a placebo. Treatments are given as soon as possible using syringe pumps (120 mL/h). The primary endpoint is the amount of blood products transfused in the first 24 h post-admission (including red blood cells, frozen fresh plasma, and platelets). The secondary endpoints are the amount of each blood product transfused in the first 24 h, time to achieve prothrombin time ratio < 1.5, time to hemostasis, number of thrombo-embolic events at 28 days, mortality at 24 h and 28 days, number of intensive care unit-free days, number of ventilator-free days, number of hospital-free days within the first 28 days, hospitalization status at day 28, Glasgow outcome scale extended for patients with brain lesions on initial cerebral imaging, and cost of each strategy at days 8 and 28. Inclusions have started in December 2017 and are expected to be complete by June 2021.DiscussionIf PCC reduces total blood consumption at day 1 after severe trauma, this therapy, in adjunction to a classic massive transfusion protocol, may be used empirically on admission in patients at risk of massive transfusion to enhance coagulation. Moreover, this treatment may decrease blood product-related complications and may improve clinical outcomes after post-traumatic hemorrhage.Trial registrationClinicalTrials.gov NCT03218722. Registered on July 14, 2017

Association between the initial serum phosphate level and 30-day mortality in blunt trauma patients.

Studies on patients with cardiac arrest or sepsis have reported that high initial phosphate levels are associated with poor outcomes. However, no previous study has investigated the association between initial phosphate levels and outcomes in blunt trauma patients. This study was a retrospective observational study conducted on blunt trauma patients who had been treated at the single regional trauma center between January 2016 and December 2017. Patients' demographic data, initial vital signs, trauma scores, and laboratory parameters including phosphate levels were collected from the trauma registry. The primary outcome was set to 30-day mortality. The secondary outcomes were the total volume of blood transfused, 30-day hospital-free days, and 30-day intensive care unit-free days. Of the 1,907 included patients, 1,836 were in the survival group, and 71 were in the nonsurvival group. The nonsurvival group had a significantly higher phosphate level than the survival group. Patients in the hyperphosphatemia group had a higher 30-day mortality, fewer 30-day intensive care unit-free days, and higher transfusion volume than those in the other groups. In multivariable logistic regression analysis, hyperphosphatemia was independently associated with 30-day mortality. The receiver operating characteristic curve analysis showed that the area under the curve with the inclusion of phosphate in addition to Injury Severity Score, Revised Trauma Score, and age was 0.911. Area under the curve was also increased when phosphate was simply added to Injury Severity Score and Revised Trauma Score. In blunt trauma patients, hyperphosphatemia was associated with an increased 30-day mortality. Prognostic, level III.

Outcomes of Patients with Sepsis in a Pediatric Emergency Department after Automated Sepsis Screening

To determine the effect of an automated sepsis screening tool on treatment and outcomes of severe sepsis in a pediatric emergency department (ED). Retrospective cohort study of encounters of patients with severe sepsis in a pediatric ED with a high volume of pediatric sepsis cases over a 2-year period. The automated sepsis screening algorithm replaced a manual screen 1year into the study. The primary outcome was the proportion of patients treated for sepsis while in the ED. Secondary outcomes were time from ED arrival to first intravenous (IV) antibiotic and first IV fluid bolus, volume of fluid administered in the ED, 30-day mortality, intensive care unit-free days, and hospital-free days. In year 1 of the study, 8910 of 61 026 (14.6%) of encounters had a manual sepsis screen; 137 patients met criteria for severe sepsis. In year 2, 100% of 61 195 encounters had an automated sepsis screen and there were 136 cases of severe sepsis. There was a higher proportion of patients with severe sepsis who had an active malignancy and indwelling central venous catheter in year 2. There were no differences in the proportion of patients treated for sepsis in the ED, time to first IV antibiotic or first IV fluid bolus, fluid volume delivered in the ED, hospital-free days, intensive care unit-free days, or 30-day mortality after implementation of the automated screening algorithm. An automated sepsis screening algorithm introduced into an academic pediatric ED with a high volume of sepsis cases did not lead to improvements in treatment or outcomes of severe sepsis in this study.

A study on the predictive value of red blood cell distribution width as a biomarker of outcome in paediatric critical illness

Background: Red blood cell distribution width (RDW) is a simple, low cost measure, which is routinely reported as a standard component of complete hemogram. Several recent studies have found a positive association between RDW and risk of both morbidity and mortality in several diseases, particularly in critically ill adults.But, data regarding the outcome predictive utility of RDW in critically ill paediatric population is limited. The objective of the study was to determine the association between RDW and mortality and morbidity in paediatric critical illness.Methods: A cross sectional observational study was conducted from February 2019-May 2019 at Cheluvamba Hospital, Mysuru. 97 subjects admitted to Paediatric intensive care unit (PICU) were included in the study. Data regarding subject demographics, hospitalization characteristics, laboratory values and outcomes were collected.Results: A significant positive correlation was found between mortality among critically ill children and RDW measured within 24 hours of PICU admission (p=0.01) and peak RDW during the first 7 days of PICU stay (p=0.01). The relative change in RDW correlated significantly (p=0.01) with the number of intensive care unit (ICU) free days. Our subjects were divided into quartiles based on the admission RDW, subjects in the fourth quartile were found to have the highest mean Paediatric risk of mortality (PRISM III) score, Paediatric index of mortality (PIM 2) score and the least number of ICU free days. Area under the receiver operator curve (AUROC) for incidence of death was 0.706 for admission RDW,0.71 for peak RDW and 0.882 for PIM 2 score.Conclusions: Our data demonstrates that RDW at the time of PICU admission could serve as a cost-effective marker for early identification of critically ill paediatric population who are at risk for adverse outcomes.

Time to tracheostomy impacts overall outcomes in patients with cervical spinal cord injury.

The morbidity associated with cervical spine injury increases in the setting of concomitant cervical spinal cord injury (CSCI). A significant proportion of these patients require placement of a tracheostomy. However, it remains unclear if timing to tracheostomy following traumatic CSCI can impact outcomes. The aim of our study was to characterize outcomes associated with tracheostomy timing following traumatic CSCI. We performed a 5-year (2010-2014) analysis of the American College of Surgeons Trauma Quality Improvement Program database and included all adult (age, ≥18 years) trauma patients who had traumatic CSCI and received tracheostomy. Patients were subdivided into two groups: early tracheostomy (ET) (≤4 days from initial intubation) and late tracheostomy (LT) (>4 days). Outcome measures included respiratory complications, ventilator-free days, intensive care unit-free days and hospital length of stay, and mortality. Multivariate logistic regression analysis was performed. A total of 5,980 patients were included in the study, of which 1,010 (17%) patients received ET, while 4,970 (83%) patients received LT. Mean age was 46 years, and 73% were men. In terms of CSCI location, 48% of the patients had high CSCI (C1-C4), while 52% had low CSCI (C5-C7). Patients in the ET group had lower rates of respiratory complications (30% vs. 46%, p = 0.01), higher ventilator-free days (13 days vs. 9 days; p = 0.02), intensive care unit-free days (11 days vs. 8 days; p = 0.01), and a shorter hospital length of stay (22 days vs. 29 days; p = 0.01) compared with those in the LT group. On regression analysis, ET was associated with lower rates of respiratory complications in patients with high CSCI (odds ratio, 0.55 [0.41-0.81]) and low CSCI (odds ratio, 0.93 [0.72-0.95]). However, no association was found between time to tracheostomy and in-hospital mortality. Early tracheostomy regardless of CSCI level may lead to improved outcomes. Quality improvement efforts should focus on defining the optimal time to tracheostomy and considering ET as a component of SCI management bundle. Therapeutic, level IV.

Study of alteplase for respiratory failure in severe acute respiratory syndrome coronavirus 2/COVID‐19: Study design of the phase IIa STARS trial

BackgroundThe coronavirus disease 2019 (COVID‐19) pandemic has caused a large surge of acute respiratory distress syndrome (ARDS). Prior phase I trials (non–COVID‐19) demonstrated improvement in pulmonary function in patients ARDS using fibrinolytic therapy. A follow‐up trial using the widely available tissue‐type plasminogen activator (t‐PA) alteplase is now needed to assess optimal dosing and safety in this critically ill patient population. ObjectiveTo describe the design and rationale of a phase IIa trial to evaluate the safety and efficacy of alteplase treatment for moderate/severe COVID‐19–induced ARDS. Patients/MethodsA rapidly adaptive, pragmatic, open‐label, randomized, controlled, phase IIa clinical trial will be conducted with 3 groups: intravenous alteplase 50 mg, intravenous alteplase 100 mg, and control (standard‐of‐care). Inclusion criteria are known/suspected COVID‐19 infection with PaO2/FiO2 ratio <150 mm Hg for > 4 hours despite maximal mechanical ventilation management. Alteplase will be delivered through an initial bolus of 50 mg or 100 mg followed by heparin infusion for systemic anticoagulation, with alteplase redosing if there is a >20% PaO2/FiO2 improvement not sustained by 24 hours. ResultsThe primary outcome is improvement in PaO2/FiO2 at 48 hours after randomization. Other outcomes include ventilator‐ and intensive care unit–free days, successful extubation (no reintubation ≤3 days after initial extubation), and mortality. Fifty eligible patients will be enrolled in a rapidly adaptive, modified stepped‐wedge design with 4 looks at the data. ConclusionFindings will provide timely information on the safety, efficacy, and optimal dosing of t‐PA to treat moderate/severe COVID‐19–induced ARDS, which can be rapidly adapted to a phase III trial (NCT04357730; FDA IND 149634).

Tranexamic acid in pediatric combat trauma requiring massive transfusions and mortality.

Tranexamic acid (TXA) has been demonstrated to decrease mortality in adult trauma, particularly in those with massive transfusions needs sustained in combat injury. Limited data are available for the efficacy of TXA in pediatric trauma patients outside of a single combat support hospital in Afghanistan. The Department of Defense Trauma Registry was queried for trauma patients younger than 18 years from Iraq and Afghanistan requiring 40 mL/kg or greater of blood product within 24 hours of injury. Burns and fatal head traumas were excluded. Primary outcome was in-hospital mortality. Secondary outcomes were hospital, ventilator, and intensive care unit-free days, as well as total blood product volume. Among those pediatric patients receiving massive transfusions, those who received TXA were less likely to die in hospital (8.5% vs. 18.3%). Patients who received TXA and those who did not have similar hospital-free days (19 vs. 20), ventilator-free days (27 vs. 27), and intensive care unit-free days (25 vs. 24). Those who received TXA had higher 24-hour blood product administration (100 mL/kg vs. 75 mL/kg). None of our results rose to the level of statistical significance. The TXA administration significantly reduced odds of death on logistic regression (odds ratio, 0.35; 95% confidence interval, 0.123-0.995; p = 0.0488). Use of TXA in pediatric patients with combat trauma requiring massive transfusions trended toward a significant improvement in in-hospital mortality (p = 0.055). This mortality benefit is similar to that seen in adult studies and a less well characterized cohort in another pediatric study suggesting TXA administration confers mortality benefit in massively transfused pediatric combat trauma victims. Evidence (retrospective cohort), Level IV.

Validating plasminogen activator inhibitor-1 as a poor prognostic factor in sepsis.

Our previous report indicated that plasminogen activator inhibitor-1 (PAI-1) levels of ≥83ng/mL in patients with sepsis tended to be associated with disseminated intravascular coagulation (DIC), suppressed fibrinolysis, multiple organ dysfunction, and mortality. Therefore, the present study aimed to validate whether 83ng/mL was a useful cut-off value for using PAI-1 levels to predict a poor prognosis in sepsis. Patients with sepsis were included in this single-center retrospective study. The patients were classified as having high or low PAI-1 values (<83ng/mL versus ≥83ng/mL), and were compared in terms of their pre-DIC state, intensive care unit-free days, continuous renal replacement therapy-free days, ventilator-free days, catecholamine-free days, and 28-day survival rate. The high PAI-1 group included 61 patients (54%) and the low PAI-1 group included 52 patients (46%). The high PAI-1 group had significantly higher frequencies of a pre-DIC state within 1week (P=0.009). There was no significant difference in ventilator-free days. However, the high PAI-1 group had significantly lower values for intensive care unit-free days (P=0.01), continuous renal replacement therapy-free days (P=0.02), and catecholamine-free days (P=0.02). The high PAI-1 group also had a significantly lower 28-day survival rate based on the Kaplan-Meier analysis (log-rank, P=0.03). Patients with sepsis and PAI-1 levels of ≥83ng/mL had elevated risks of coagulopathy, organ failure, and mortality. Thus, these results suggest that 83ng/mL could be a useful cut-off value for prognostication based on PAI-1 levels in this setting.

Positive Fluid Balance is Associated with Poor Clinical Outcomes in Paediatric Severe Sepsis and Septic Shock

Growing evidence suggests there is potential harm associated with excess fluid in critically ill children. This study aimed to evaluate the association between percentage fluid overload (%FO) and paediatric intensive care unit (PICU) mortality in children with severe sepsis and septic shock. Patients with severe sepsis and septic shock admitted to the PICU were identified through discharge codes. Data on clinical characteristics, fluid input and output were collected. %FO was calculated as: (total daily input - total daily output [L]/admission body weight [kg]) × 100. The primary outcome was PICU mortality. Secondary outcomes were 28-day ventilator-free days (VFD), intensive care unit-free days (IFD) and inotrope-free days (InoFD). Multivariate analysis adjusting for presence of comorbidities, Pediatric Index of Mortality (PIM) 2 score and multiorgan dysfunction were used to determine the association between cumulative %FO over 5 days and outcomes. A total of 116 patients were identified, with a mortality rate of 28.4% (33/116). Overall median age was 105.9 (23.1-157.2) months. Cumulative %FO over 5 days was higher in non-survivors compared to survivors (median [interquartile range], 15.1 [6.3-27.1] vs 3.6 [0.7-11.1]%; P <0.001). Cumulative %FO was associated with increased mortality (adjusted odds ratio 1.08, 95% confidence interval 1.03-1.13; P = 0.001) and decreased VFD, IFD and InoFD (adjusted mean difference -0.37 [-0.53 - -0.21] days, -0.34 [-0.49 - -0.20] days, and -0.31 [-0.48 - -0.14] days, respectively). Cumulative %FO within the first 5 days of PICU stay was consistently and independently associated with poor clinical outcomes in children with severe sepsis and septic shock. Future studies are needed to test the impact of restrictive fluid strategies in these children.