MC3 (United States)

Lessons from the implementation of a critical care registry to support high-quality health systems in Asia 3

BackgroundStored red blood cells (RBCs) may undergo oxidative stress over time, with functional changes affecting oxygen delivery. Central to these changes are oxidation‐reduction (redox) reactions and redox potential (RP) that must be maintained for cell function. RP imbalance can lead to oxidative stress that may contribute to storage lesions. This study's purpose was to identify changes in RP over time in banked RBCs, and among RBCs of similar age.MethodsMultiple random RBC segments from RBC units were tested (n = 32), ranging in age from 5 to 40 days, at 5‐day intervals. RP was recorded by measuring open circuit potential of RBCs using nanoporous gold electrodes with Ag/AgCl reference. RP measures were also performed on peripheral venous blood from 10 healthy volunteers. RP measures were compared between RBC groups, and with volunteer blood.ResultsStored RBCs show time‐dependent RP increases. There were significant differences in Day 5 RP compared to all other groups (p ≤ 0.005), Day 10–15 vs. ages ≥ Day 20 (p ≤ 0.025), Day 20–25 vs. Day 40 (p = 0.039), and all groups compared to healthy volunteers. RP became more positive over time suggesting ongoing oxidation as RBCs age; however, storage time alone was not predictive of RP measured in a particular unit/segment.ConclusionsThere are significant differences in RP between freshly stored RBCs and all others, with RP becoming more positive over time. However, storage time alone does not predict RP, indicating RP screening may be an important measure of RBC oxidative stress and serve as an RBC quality marker.

BackgroundThe coronavirus disease 2019 (COVID‐19) pandemic has resulted in millions of deaths and overburdened healthcare systems worldwide. Systemic low‐dose corticosteroids have proven clinical benefit in patients with severe COVID‐19. Higher doses of corticosteroids are used in other inflammatory lung diseases and may offer additional clinical benefits in COVID‐19. At present, the balance between benefits and harms of higher vs. lower doses of corticosteroids for patients with COVID‐19 is unclear.MethodsThe COVID STEROID 2 trial is an investigator‐initiated, international, parallel‐grouped, blinded, centrally randomised and stratified clinical trial assessing higher (12 mg) vs. lower (6 mg) doses of dexamethasone for adults with COVID‐19 and severe hypoxia. We plan to enrol 1,000 patients in Denmark, Sweden, Switzerland and India. The primary outcome is days alive without life support (invasive mechanical ventilation, circulatory support or renal replacement therapy) at day 28. Secondary outcomes include serious adverse reactions at day 28; all‐cause mortality at day 28, 90 and 180; days alive without life support at day 90; days alive and out of hospital at day 90; and health‐related quality of life at day 180. The primary outcome will be analysed using the Kryger Jensen and Lange test adjusted for stratification variables and reported as adjusted mean differences and median differences. The full statistical analysis plan is outlined in this protocol.DiscussionThe COVID STEROID 2 trial will provide evidence on the optimal dosing of systemic corticosteroids for COVID‐19 patients with severe hypoxia with important implications for patients, their relatives and society.

The objective of this review is to discuss the therapeutic use and differential treatment response to Levo-carnitine (l-carnitine) treatment in septic shock, and to demonstrate common lessons learned that are important to the advancement of precision medicine approaches to sepsis. We propose that significant interpatient variability in the metabolic response to l-carnitine and clinical outcomes can be used to elucidate the mechanistic underpinnings that contribute to sepsis heterogeneity. A narrative review was conducted that focused on explaining interpatient variability in l-carnitine treatment response. Relevant biological and patient-level characteristics considered include genetic, metabolic, and morphomic phenotypes; potential drug interactions; and pharmacokinetics (PKs). Despite promising results in a phase I study, a recent phase II clinical trial of l-carnitine treatment in septic shock showed a nonsignificant reduction in mortality. However, l-carnitine treatment induces significant interpatient variability in l-carnitine and acylcarnitine concentrations over time. In particular, administration of l-carnitine induces a broad, dynamic range of serum concentrations and measured peak concentrations are associated with mortality. Applied systems pharmacology may explain variability in drug responsiveness by using patient characteristics to identify pretreatment phenotypes most likely to derive benefit from l-carnitine. Moreover, provocation of sepsis metabolism with l-carnitine offers a unique opportunity to identify metabolic response signatures associated with patient outcomes. These approaches can unmask latent metabolic pathways deranged in the sepsis syndrome and offer insight into the pathophysiology, progression, and heterogeneity of the disease. The compiled evidence suggests there are several potential explanations for the variability in carnitine concentrations and clinical response to l-carnitine in septic shock. These serve as important confounders that should be considered in interpretation of l-carnitine clinical studies and broadly holds lessons for future clinical trial design in sepsis. Consideration of these factors is needed if precision medicine in sepsis is to be achieved.

High-dose valproic acid in combination with hypothermic-targeted temperature management has been reported to synergistically improve neurologic outcomes after cardiac arrest. This study investigated the potential synergistic mechanisms. Prospective, randomized, experimental study. University research institution. Male Long Evans rats. Rats resuscitated from asphyxial cardiac arrest were randomized to one of the three groups: normothermic-targeted temperature management (37°C ± 1°C), hypothermic-targeted temperature management (33° ± 1° × 24 hr + placebo infusion), hypothermic-targeted temperature management plus high-dose valproic acid (300 mg/kg IV × 1 initiated 5 min post return of spontaneous circulation and infused over 20 min) (hypothermic-targeted temperature management + valproic acid). Seventy-two-hour survival was significantly greater with hypothermic-targeted temperature management + valproic acid, compared to hypothermic-targeted temperature management and normothermic-targeted temperature management (p < 0.05). Survival with good neurologic function, neurodegeneration, expression of HSP70, phosphorylation of Akt and Erk1/2 were not significantly different between hypothermic-targeted temperature management and hypothermic-targeted temperature management + valproic acid. The prevalence of seizures during the first 72-hour postcardiac arrest was significantly lower with hypothermic-targeted temperature management + valproic acid compared to hypothermic-targeted temperature management and normothermic-targeted temperature management (p = 0.01). High-dose valproic acid combined with hypothermic-targeted temperature management prevents postcardiac arrest seizures and improves survival. It remains to be determined if the mechanism of seizure prevention is through the antiepileptic effect of valproic acid or direct neuroprotection. Overall, the combination of high-dose valproic acid and hypothermic-targeted temperature management remains a promising strategy to improve cardiac arrest outcomes.

Donation from uncontrolled circulatory determination of death donors (uDCD) is impractical in United States because of the time needed to organize procurement before irreversible organ damage. Salvaging organs after prolonged warm ischemic time (WIT) may address this limitation. We evaluated the combination of extracorporeal support (ECS) and thrombolytics in a porcine uDCD renal transplant model. Nonanticoagulated uDCD sustained 60 min of WIT, and two groups were studied. Rapid recovery (RR)-uDCD renal grafts procured using the standard quick topical cooling and renal flush, and ECS-assisted donation (E-uDCD), 4 hr ECS plus thrombolytics for in situ perfusion before procurement. All kidneys were flushed and cold stored, followed by transplantation into healthy nephrectomized recipients without immunosuppression. Delayed graft function (DGF) was defined as creatinine more than 5.0 mg/dl on any postoperative day. Twelve kidneys in E-uDCD and 6 in RR-uDCD group were transplanted. All 12 E-uDCD recipients had urine production and adequate function in the first 48 hr, but two grafts (16.7%) had DGF at 96 hr. All six recipients from RR-uDCD group had DGF at 48 hr and were killed. Creatinine and blood urea nitrogen (BUN) levels were significantly lower in E-uDCD compared with RR-uDCD group at 24 hr (2.9 ± 0.7 mg/dl vs. 5.2 ± 0.9 mg/dl) and 48 hr (3.2 ± 0.9 mg/dl vs. 7.2 ± 1.0 mg/dl); BUN levels at 24 and 48 hr were 28.3 ± 6.7 mg/dl vs. 39.5 ± 7.5 mg/dl and 23.9 ± 5.0 mg/dl vs. 46 ± 12.9 mg/dl, respectively. Thrombolytics plus ECS precondition organs in situ yielding functional kidneys in a porcine model of uDCD with 60 min of WIT. This procurement method addresses logistical limitations for uDCD use in the United States and could have a major impact on the organ donor pool.

Journal of Esthetic and Restorative DentistryVolume 24, Issue 6 p. 363-364 PERSPECTIVES In Vitro Testing of Restorative Materials—What's the Value? JOHN M. POWERS PHD, JOHN M. POWERS PHD Clinical Professor of Oral Biomaterials, Senior Editor, The Dental Advisor, Section Editor of Dental Materials, JERDSearch for more papers by this author JOHN M. POWERS PHD, JOHN M. POWERS PHD Clinical Professor of Oral Biomaterials, Senior Editor, The Dental Advisor, Section Editor of Dental Materials, JERDSearch for more papers by this author First published: 22 October 2012 https://doi.org/10.1111/jerd.12002 Reprint requests: John M. Powers, PhD, Dental Consultants, Inc., 3110 W. Liberty Street, Ann Arbor, MI 48103, USA; Tel.: 734-665-2020 (Ext. 113); Fax: 734-665-1648; email: jpowers@dentaladvisor.com Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume24, Issue6December 2012Pages 363-364 RelatedInformation

Our group has developed a paracorporeal artificial lung (PAL) attached in a pulmonary artery (PA) to PA in series configuration to address profound respiratory failure and serve as a bridge to transplant and/or recovery. We recently designed, developed and converted our passive pre-PAL compliance chamber to an active, synchronized, counterpulsating assist device to relieve right heart strain and offset increased work placed on the right ventricle when the PAL is attached. In this study, we evaluated the safety and performance of both a valved and non-valved optional active compliance chamber (OACC) in a PA-PA PAL for right heart assistance in normal adult sheep. Eleven sheep (30-50 kg) were divided into non-valved OACC (n = 6) and valved (n = 5) OACC groups. To mimic pulmonary hypertension, a C-clamp was placed distal to the OACC-PAL and occluded until a 20% decrease in cardiac output (CO) was achieved. The OACC was activated, and right ventricular pressure (RVP), pulmonary artery pressure (PAP), mean arterial pressure (MAP) and CO were recorded. All eleven animals tolerated the implantation of the OACC PAL. Activation of the OACC resulted in a significant increase in CO. Systolic and diastolic right ventricular pressure decreased in both groups. Lastly, counterpulsation increased the mean PAP in all animals and peak PAP reached 89 mmHg. Despite providing right heart assistance, synchronizing the counterpulsation was technically difficult, and the high peak PA pressures resulted in anastomotic bleeding in all animals and anastomotic breakdown in 4/11 animals. An OACC PAL perfused by the right ventricle applied in series with the pulmonary circulation reduces ventricular load and improves cardiac efficiency. These preliminary data suggest the potential of an artificial lung in unloading the strained right ventricle and acting as a bridge to transplantation. The augmented peak PA pressures, resulting in bleeding and anastomotic breakdown, and complexity in synchronizing the cardiac cycle with the pulsations of the augmented OACC, compromise this configuration.