Does Early Goal-Directed Therapy Decrease Mortality Compared with Standard Care in Patients with Septic Shock?

Background

Current international guidelines for the treatment of patients with severe sepsis and septic shock recommend that patients receive targeted care to various physiologic endpoints, thereby optimizing tissue perfusion and oxygenation. These recommendations are primarily derived from a protocol published >15 years ago, which was viewed by many as complex and was therefore not widely adopted. Instead, many emergency physicians focused on the administration of early antibiotics, source control, aggressive fluid resuscitation, vasoactive medications as needed to maintain mean arterial blood pressure, and careful monitoring of these patients. The primary goal of this literature search was to determine if there is a mortality benefit to the early goal-directed protocol recommended by current international sepsis guidelines compared to current usual care.

A Model of the Kinetics of Insulin in Man

The design of the present study of the kinetics of insulin in man combines experimental features which obviate two of the major problems in previous insulin studies. (a) The use of radioiodinated insulin as a tracer has been shown to be inappropriate since its metabolism differs markedly from that of the native hormone. Therefore porcine insulin was administered by procedures which raised insulin levels in arterial plasma into the upper physiologic range. Hypoglycemia was prevented by adjusting the rate of an intravenous infusion of glucose in order to control the blood glucose concentration (the glucose-clamp technique). (b) Estimation of a single biological half-time of insulin after pulse injection of the hormone has been shown to be inappropriate since plasma insulin disappearance curves are multiexponential. Therefore the SAAM 25 computer program was used in order to define the parameters of a three compartment insulin model.The combined insulin mass of the three compartments (expressed as plasma equivalent volume) is equal to inulin space (15.7% body wt). Compartment 1 is apparently the plasma space (4.5%). The other two compartments are extra-vascular; compartment 2 is small (1.7%) and equilibrates rapidly with plasma, and compartment 3 is large (9.5%) and equilibrates slowly with plasma.The SAAM 25 program can simulate the buildup and decay of insulin in compartments 2 and 3 which cannot be assayed directly. Insulin in compartment 3 was found to correlate remarkably with the time-course of the servo-controlled glucose infusion. Under conditions of a steady-state arterial glucose level, glucose infusion is a measure of glucose utilization. We conclude that compartment 3 insulin (rather than plasma insulin) is a more direct determinant of glucose utilization.We suggest that the combined use of glucose-clamp and kinetic-modeling techniques should aid in the delineation of pathophysiologic states affecting glucose and insulin metabolism.     

The Salvage of Heparinized Blood with Acid-Citrate-Dextrose

Heparinized blood not used at operation may be salvaged by transfer to Acid-Citrate-Dextrose (ACD) within 24 hours after collection. Collection and transfer must be done in a closed system and adequate refrigeration maintained from collection to transfusion. In five experiments, post-transfusion survival studies have shown the percentage of viable cells to fall to 70 per cent in about 12 days. Plasma p H, hemoglobin, and potassium levels were within the same range as those of ACD bloods stored for similar periods. Of 180 heparinized bloods not used because of changes in operative schedules, 158 were salvaged and transfused, within this limit, in other cases.     

Brain dynamics of post‐task resting state are influenced by expertise: Insights from baseball players

Post‐task resting state dynamics can be viewed as a task‐driven state where behavioral performance is improved through endogenous, non‐explicit learning. Tasks that have intrinsic value for individuals are hypothesized to produce post‐task resting state dynamics that promote learning. We measured simultaneous fMRI/EEG and DTI in Division‐1 collegiate baseball players and compared to a group of controls, examining differences in both functional and structural connectivity. Participants performed a surrogate baseball pitch Go/No‐Go task before a resting state scan, and we compared post‐task resting state connectivity using a seed‐based analysis from the supplementary motor area (SMA), an area whose activity discriminated players and controls in our previous results using this task. Although both groups were equally trained on the task, the experts showed differential activity in their post‐task resting state consistent with motor learning. Specifically, we found (1) differences in bilateral SMA–L Insula functional connectivity between experts and controls that may reflect group differences in motor learning, (2) differences in BOLD‐alpha oscillation correlations between groups suggests variability in modulatory attention in the post‐task state, and (3) group differences between BOLD‐beta oscillations that may indicate cognitive processing of motor inhibition. Structural connectivity analysis identified group differences in portions of the functionally derived network, suggesting that functional differences may also partially arise from variability in the underlying white matter pathways. Generally, we find that brain dynamics in the post‐task resting state differ as a function of subject expertise and potentially result from differences in both functional and structural connectivity. Hum Brain Mapp 37:4454–4471, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.     

Does insulin species modify counterregulatory hormone response to hypoglycemia?

OBJECTIVE: To examine whether pork and human insulin induce different counterregulatory responses to hypoglycemia. RESEARCH DESIGN AND METHODS: The responses to a mild hypoglycemic stimulus were determined in 35 healthy young adults with the glucose-clamp technique to ensure standardization of glucose and insulin levels. Either pork (n = 15) or human (n = 20) regular insulin was infused (0.8 mU.kg-1.min-1) to lower plasma glucose from 4.7 +/- 0.07 to 3.3 +/- 0.04 mM (both groups) over approximately 40 min. Plasma glucose was maintained at that level (with variable rate glucose infusion) for an additional 60 min. RESULTS: Steady-state insulin levels were similar in both groups (316 +/- 50 vs. 280 +/- 29 pM, pork vs. human). Before insulin administration, basal counterregulatory hormone levels were indistinguishable. Most importantly, after plasma glucose was lowered, hormonal responses were nearly identical. No significant differences in peak values of epinephrine (1769 +/- 404 vs. 1775 +/- 311 pM, pork vs. human), norepinephrine (1.64 +/- 0.23 vs. 1.87 +/- 0.20 nM, pork vs. human), glucagon (163 +/- 29 vs. 175 +/- 20 ng/L, pork vs. human), growth hormone (14 +/- 3 vs. 17 +/- 3 micrograms/L, pork vs. human), or cortisol (543 +/- 83 vs. 458 +/- 28 nM, pork vs. human) occurred. CONCLUSIONS: Our data suggest that pork and human insulin produce a comparable and robust hormonal response in healthy adults under conditions of controlled hypoglycemia.     

A simple binding assay for the direct determination of biotin in urine

BACKGROUND: We have devised a simple assay to detect adequate biotin intake, which uses an alternative configuration from most existing assays. METHODS: The assay depends on the competition of streptavidin peroxidase for immobilized biotin or soluble biotin in standards or samples. Immobilized streptavidin peroxidase is detected using tetramethylbenzidine, and the plates are read at 450 nm. The assay was normalised by determining the biotin/creatinine ratio in the urine of healthy adults. Urinary biotin excretion was measured in unsupplemented pregnant women. The half-life of biotin excretion after a single oral supplement was determined for healthy volunteers. RESULTS: Urinary biotin excretion in unsupplemented pregnant women was 2.9+/-1.9 micromol/mol creatinine (mean+/-S.D.) and was significantly lower (p<0.001) than those of healthy males and females, which were 9.0+/-5.4 and 7.0+/-2.1 micromol/mol creatinine (mean+/-S.D.), respectively. The half-life of a single oral biotin supplement was 30-40 h, with excretion returning to basal levels at 70 h. CONCLUSION: We have devised a novel binding assay for the direct determination of total biotin excretion in urine, which is suitable for routine clinical laboratory. The assay is inexpensive, simple, rapid, and could be fully automated.     

A Clinical Evaluation of the Use of Citrate-Phosphate-Dextrose Solution in Children

Red cells collected in CPD anticoagulant have been shown to have a mean postinfusion survival of greater than 75 per cent after 28 days of storage at 4C, in contrast to blood collected in ACD solution whose mean survival is less than 70 per cent after 28 days.
In a clinical study, 3,704 units of CPD blood collected in double plastic blood packs were utilized for 4,354 transfusions in 2,425 children. Evaluation of the stability of red cell antigens disclosed that blood preserved in CPD showed a minimal loss of antigenicity after 28 days. In contrast, clotted samples were hemolyzed and demonstrated marked loss of antigenicity for Kell, hr'(c) and P after 14 days.
Whole blood preserved in CPD provides two basic advantages over the presently used ACD solution. It provides a more physiologic blood for the recipient and has decreased the outdating percentage by better than 65 per cent.     

Critical need for pharmacologic treatment options in NAFLD: A pediatric perspective

Nonalcoholic fatty liver disease (NAFLD) affects up to 70% of children with obesity and has become the number one etiology for liver transplant in the United States. Early, effective intervention is critical to prevent disease progression into adulthood. Yet, it is seldom achieved through lifestyle modification alone. Thus, children must be included in NAFLD pharmacology trials, which, to date, continue to focus primarily on adult populations. This commentary serves as a call to action.

Three hundred forty million children worldwide are affected by overweight/obesity (https://www.who.int/end‐childhood‐obesity/publications/taking‐action‐childhood‐obesity‐report/en/). Without intervention, > 75% of these children will continue to gain excessive weight and become adults with obesity. ¹ Alarmingly, almost all adults with obesity (90%) develop comorbid nonalcoholic fatty liver disease (NAFLD), the leading etiology for liver transplant in the United States. ² Thus, effective, early life intervention is critical for children with obesity, up to 70% of whom already have comorbid NALFD by adolescence. ² Lifestyle modifications (e.g., diet and exercise) resulting in weight loss of as little as one kilogram can improve NAFLD in children. ³ However, overall adherence to lifestyle modification is low, with the exception of a few pediatric research studies that offer intense follow‐up ³ , ⁴ or comprehensive in‐home services. ⁴ As such, bariatric surgery is increasingly recognized as an option for weight reduction in children, but it is invasive and there is an unpredictable subset of patients who experience worsening liver fibrosis and NAFLD progression postsurgery. ⁵ This leaves a critical, unmet need for effective pharmacologic interventions in pediatric NAFLD.Currently, there are no approved medications for NAFLD; however, the landscape of potential therapeutic agents is evolving rapidly and showing promise, as highlighted in a comprehensive review by Attia et al. published in Clinical and Translational Science. ⁶ In addition to the many novel therapeutic agents discussed (e.g., obeticholic acid, fibroblast growth factor 19 and 21 analogues, thyroid hormone receptor‐β agonists, etc.), the authors briefly mention past therapeutic experiences with medications already on the market for other clinical indications. Although the adult experience with some of these medications was equivocal, it is important to note that some agents show promise for repurposing in pediatric NAFLD.One example is metformin, a drug already approved for the treatment of type 2 diabetes in children > 10 years of age. In a study of lifestyle modifications combined with either metformin or placebo in children with obesity and insulin resistance ± NAFLD, the metformin group demonstrated a significant decrease in NAFLD scores and NAFLD prevalence, whereas the placebo group experienced an increase from baseline for both. ⁷ Interestingly, when metformin was administered at lower doses in other pediatric trials, it demonstrated isolated improvement in histopathology features (e.g., hepatic ballooning), ⁸ but not in the overall histopathology NAFLD score, suggesting that metformin’s effect on NAFLD may be dose dependent. Therefore, further studies of metformin in the setting of pediatric NAFLD are indicated.Other drugs already approved for obesity‐related comorbidities may also be of interest for repurposing in pediatric NAFLD. Statins, cholesterol‐lowering agents prescribed to patients with obesity and hypercholesterolemia, have been shown to significantly improve hepatic function in patients with obesity and NAFLD ⁹ —presumably through anti‐inflammatory mechanisms in the liver. Although no data are available in pediatrics, in adults with NAFLD, statin therapy is well‐tolerated, with low frequency of hepatotoxicity similar to placebo, ⁹ making statins intriguing drug candidates to consider for the treatment of pediatric NAFLD. Secondary analyses of off‐target treatment effects of medications already prescribed to children with obesity (e.g., statins and metformin) may be helpful in uncovering important insights into therapeutic options for pediatric NAFLD treatment. Especially while best practices for expanding novel NAFLD therapeutics trials to pediatrics remain under development, as referenced in a recent draft guidance from the US Food and Drug Administration (https://www.fda.gov/media/119044/download).In our opinion, and the opinion of other experts, ¹⁰ inclusion of pediatric populations in adult NAFLD pharmacology trials is important and represents a strategy that has been successfully implemented in oncology trials. Yet, the majority of new NAFLD agents continue to be pursued more aggressively for adults than children. As illustrated in the review by Attia et al., ⁶ only 2 of the 17 therapeutic trials discussed included children. By excluding children, we are missing a critical opportunity for early intervention to prevent NAFLD progression from simple hepatic steatosis to more advanced disease (i.e., steatohepatitis, fibrosis, cirrhosis, hepatocellular carcinoma, and end‐stage liver failure). Our hope is that increased awareness of pediatric NAFLD prevalence, coupled with the National Institutes of Health policy for inclusion of research subjects across the lifespan (https://grants.nih.gov/policy/inclusion/lifespan.html), will encourage investigators to include pediatric patients in clinical trials of NAFLD therapeutics.Inclusion of children in pharmacology trials comes with its own set of unique challenges and nuances (e.g., ontogeny, age‐appropriate outcome measures, parental informed consent and informed assent of minors, etc.), beyond the scope of this commentary and as comprehensively reviewed in a pediatric tutorial guide by Shakhnovich et al. ¹¹ In addition, to facilitate inclusion of children specifically in pharmacology trials for NAFLD, NAFLD‐specific noninvasive biomarkers are urgently needed. The majority of studies reviewed by Attia et al. ⁶ relied on histopathology‐based assessment of NAFLD as a therapeutic outcome measure. However, liver biopsy is invasive and histopathology assessment is not always feasible or ethical in children, especially in the context of research. Alanine aminotransferase, the most commonly utilized clinical serum biomarker of liver injury is nonspecific for NAFLD. Therefore, several more‐specific biomarkers are currently under investigation; among them, serum bile acids. Total fasting and postprandial bile acids, and the ratios of conjugated and secondary bile acids, are consistently higher in the sera of adults with nonalcoholic hepatic steatosis, compared with healthy controls. ¹² Pediatric studies of bile acids lag behind, are sparse and inconsistent, and are needed to establish minimally invasive biomarkers of NAFLD for children.Recently, noninvasive liver imaging biomarkers have become more widely available, and it is encouraging to see these modalities incorporated into NAFLD therapeutics research, including four trials discussed by Attia et al. ⁶ Both ultrasound elastography and magnetic resonance elastography can quantify liver stiffness as a noninvasive surrogate for liver fibrosis. However, NAFLD presents a challenge to both techniques because elastography values are affected by both fat and fibrosis. Magnetic resonance proton density fat fraction (MR‐PDFF) can directly estimate hepatic fat content and allows clinicians and researchers to separate the individual contributions from fat vs. fibrosis to liver stiffness. However, MR‐PDFF is only available in specialized tertiary care centers and is expensive. Ultrasound techniques for fat quantification could offer a cheaper, more readily available alternative to MR‐PDFF and these techniques are likely to become widely available in the near future.Thus, the landscape of therapeutic pharmacology trials for NAFLD is rapidly evolving. The advent of noninvasive biomarkers for monitoring NAFLD treatment response offers promise and opportunity, especially for inclusion of pediatric patients in research. A concerted effort must be made to include children in NAFLD pharmacology trials, as NAFLD affects up to 70% of children with obesity, ² and early childhood intervention is key to minimize/reverse disease progression to end‐stage liver disease in adulthood.