Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016

OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012". DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy wasdeveloped at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroupsand among the entire committee served as an integral part of the development. METHODS: The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. RESULTS: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. CONCLUSIONS: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.(AU)

Defining biomedical informatics competency: the foundations of a profession.

Is biomedical informatics a science or a profession? This question has been asked of many members in the biomedical informatics community, yet we still lack a response that galvanizes our community. We debate the issues over lunch. We create long, multi-threaded e-mail discussions, we write papers on the topic, and still we aren't able to convince ourselves-let alone the rest of the scientific community. In this paper, I will describe a curriculum model for biomedical informatics and research that is developing at Columbia University, Department of Biomedical Informatics (DBMI). We believe that a strong educational foundation creates competent professionals who, in turn, comprise a bioinformatics culture. The outcome of DBMI's curriculum design and competency project will be a set of biomedical informatics competencies which we believe will define the core knowledge and skills of the field.

The Arabidopsis embryo mutant schlepperless has a defect in the chaperonin-60alpha gene.

We identified a T-DNA-generated mutation in the chaperonin-60alpha gene of Arabidopsis that produces a defect in embryo development. The mutation, termed schlepperless (slp), causes retardation of embryo development before the heart stage, even though embryo morphology remains normal. Beyond the heart stage, the slp mutation results in defective embryos with highly reduced cotyledons. slp embryos exhibit a normal apical-basal pattern and radial tissue organization, but they are morphologically retarded. Even though slp embryos are competent to transcribe two late-maturation gene markers, this competence is acquired more slowly as compared with wild-type embryos. slp embryos also exhibit a defect in plastid development-they remain white during maturation in planta and in culture. Hence, the overall developmental phenotype of the slp mutant reflects a lesion in the chloroplast that affects embryo development. The slp phenotype highlights the importance of the chaperonin-60alpha protein for chloroplast development and subsequently for the proper development of the plant embryo and seedling.

Management issues in toxicology.

The lack of evidence-based information in toxicology results in debate and differing recommendations on management issues. Gastric lavage is often utilized to remove toxins from the stomach but a clinical benefit of the procedure has not been definitively demonstrated. A selective approach is warranted in each patient, and gastric lavage can be considered in patients with life-threatening ingestions if it can be performed within 60 minutes of ingestion. Whole bowel irrigation is a method of GI decontamination utilizing isotonic electrolyte solution. Although safe, there is currently insufficient data to establish definite indications for use. This technique can be considered for potentially toxic ingestions of lithium, iron, and sustained-release or enteric-coated drugs. Multiple-dose activated charcoal has been used to enhance elimination of drugs already absorbed into the body but the optimum dose and frequency of administration is not established. Based on volunteer studies and limited clinical reports, multiple-dose activated charcoal may be considered in patients with life-threatening ingestions of carbamazepine, dapsone, phenobarbital, quinine, or theophylline. A variety of interventions in addition to hemodialysis have been proposed to enhance lithium elimination. Forced saline diuresis and diuretics are not indicated. Although studies suggest that sodium polystyrene sulfonate may enhance elimination of lithium, no beneficial effects on clinical outcomes have been demonstrated and potential complications include hypokalemia and hypernatremia. Blood alkalinization for cyclic antidepressant toxicity has become standard therapy. Alkalinization is most effective in treating significant cardiac toxicity. Sodium bicarbonate, rather than hyperventilation, should be used initially to alkalinize blood. The benefit of blood alkalinization in the treatment of hypotension and seizures is not established.

Phase I trial of the recombinant soluble complement receptor 1 in acute lung injury and acute respiratory distress syndrome.

OBJECTIVE: To determine the safety, pharmacokinetics, biological effects, and immunogenicity of recombinant soluble complement receptor 1 (TP10) in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). DESIGN: Open label, ascending dosage, phase I trial. SETTING: Two academic teaching hospitals. PATIENTS: A total of 24 patients diagnosed with ALI/ARDS. INTERVENTION: A single, 30-min intravenous infusion of 0.1, 0.3, 1, 3, or 10 mg/kg TP10. MEASUREMENTS AND MAIN RESULTS: Serum levels of TP10 increased in proportion to the dose. Mean variable estimates (+/-SD) were half-life of disposition 69.7 +/- 39.7 hrs, plasma clearance 2.39 +/- 1.32 mL/hr/kg, and volume of distribution 190.6 +/- 135.0 mL/kg. Inhibition of complement activity, measured by CH50, was significant for the interaction of dose and time (p = .024). The C3a levels demonstrated a trend for dose which did not reach statistical significance (p = .090) and soluble C5b-9 levels were significant only for dose (p = .023). As expected by the proposed physiologic mechanism, C4a levels were not affected by TP10, dose, or time. The overall mortality rate was 33%. Neither the type nor the frequency rate of specific adverse events were substantially different between dose groups. Seven adverse events in four patients were thought to be possibly related to TP10. CONCLUSIONS: TP10 has a half-life of approximately 70 hrs and at doses > or =1 mg/kg, significantly inhibits complement activity at the levels of C3 and C5 in patients with ALI/ARDS. Complement inhibition was more prolonged over time with TP10 doses of 3 and 10 mg/kg. TP10 appears to be safe at the doses tested. Further studies will be required to completely assess the impact of TP10 on pathophysiology and clinical outcome in patients with ALI/ARDS.

Relation between phase of menstrual cycle and emergency department visits for acute asthma.

Hormonal fluctuations during the menstrual cycle are hypothesized to influence the course of asthma among women. A recent study found that almost 50% of emergency department (ED) visits occur during the perimenstrual phase. Our prospective cohort study in 64 EDs examined the relation between phase of menstrual cycle and visits for acute asthma. A total of 288 women with acute asthma were evaluated with a standardized patient interview and medical record review after excluding subjects who were pregnant, on hormonal therapy, postmenopausal, status post hysterectomy, had incomplete reproductive data, or whose ED visit fell more than 28 d after their last menstrual period. Only 13% reported reproductive factors as a personal asthma trigger. For all subjects, ED asthma visits were classified by menstrual phase: 33% were preovulatory (Days 5 to 11), 26% were periovulatory (Days 12 to 18), 20% were postovulatory (Days 19 to 25), and 21% were perimenstrual (Days 26 to 4), p = 0.008. There was no significant association between phase of menstrual cycle and asthma severity. Our data indicate that ED visits for acute asthma among women are more frequent during the preovulatory phase in contrast to other studies reporting more visits in the perimenstrual phase.

Accidental hypothermia.

Individuals at extremes of age and those who have certain underlying medical conditions are at greatest risk for hypothermia. Hypothermia may occur during any season of the year and in any climate. Prompt recognition of hypothermia and early institution of the rewarming techniques are imperative for a successful outcome with minimal complications. Several rewarming techniques are available and the decision to use any of them depends on the degree of hypothermia, the condition of the patient, and the rewarming rate possible with the technique chosen.

Respiratory tract viral infections in inner-city asthmatic adults.

BACKGROUND: Respiratory tract viral infections (RTVIs) have been identified frequently in association with asthma exacerbations in children, but few studies have shown similar rates of viral infections in adults with asthma. Further studies using newer diagnostic techniques to evaluate the frequency of RTVIs in adults with acute exacerbations of asthma need to be performed. METHODS: Twenty-nine asthmatic adults were recruited from the pulmonary clinic of an urban county hospital and were followed up in a longitudinal cohort study for signs and symptoms of asthma and RTVI. One hundred twenty-two asthmatic adults presenting to the emergency department (ED) of the same hospital with acute symptoms of asthma underwent evaluation for RTVI in a cross-sectional prevalence study. In both studies, respiratory secretions and paired serum samples were collected from subjects with acute wheezing episodes and evaluated using virus culture, serologic testing, and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: In the longitudinal cohort study, 138 respiratory illnesses, of which 87 were asthma exacerbations, were evaluated; 41% of all illnesses and 44% of asthma exacerbations were associated with an RTVI. In the ED study, 148 asthma exacerbations were evaluated; 55% were associated with an RTVI. An RTVI was identified in 21 (50%) of 42 of the subjects hospitalized in the ED study. Picornaviruses (rhinoviruses), coronaviruses, and influenza viruses were the most commonly identified causes of RTVI. Forty-six (60%) of the 77 picornavirus infections and 22 (71%) of the 31 coronavirus infections were identified only using RT-PCR. CONCLUSIONS: Asthmatic exacerbations in adults are frequently associated with an RTVI. Identification of such infections often requires newer diagnostic methods, such as virus-specific RT-PCR. The high frequency of RTVIs identified in association with asthmatic exacerbations in adults from the inner city suggests that strategies for the prevention of RTVI should be targeted toward this population.

Sirolimus (rapamycin, Rapamune) and combination therapy with cyclosporin A in the rat developing adjuvant arthritis model: correlation with blood levels and the effects of different oral formulations.

OBJECTIVE AND DESIGN: To determine whole blood levels of sirolimus, a macrolide antibiotic in the rat developing adjuvant arthritis (AA) model after dosing orally with two different vehicles, and whether combinational doses of sirolimus and cyclosporin A (CsA) produced additive or synergistic inhibitory effects in this model. MATERIAL: Male Lewis rats (150-180g). TREATMENT: Arthritis was induced by the injection (0.5 mg/ rat) of heat-killed Mycobacterium butyricum suspended in light mineral oil. Drugs were administered orally either in fine suspension (0.5% Tween 80) or in emulsion (phosal 50 PG in 1% Tween 80) at doses of 0.1 to 5 mg/kg in a 7 day, MWF or daily regimen. METHOD: Paw volumes (ml) were measured by automated mercury plethysmograph and sirolimus concentrations in whole blood were quantitated by liquid chromatography/ mass spectroscopy. RESULTS: At 72h (7 days after adjuvant) after receiving the third oral dose (4.5 mg/kg p.o.), the phosal vehicle resulted in higher sirolimus blood levels (2.5 ng/ml) than in Tween 80 (1.6 ng/ml). After the rats received the last oral dose on day 14, (7 total doses of sirolimus at 4.5 mg/kg) the sirolimus blood levels (2h after the last dose) were about 2 times higher for the phosal dosed rats (9.8 ng/ml) compared to Tween 80 dosed rats (4.6ng/ml). Even 24h after the last dose, sirolimus blood levels were still elevated in the phosal dosed rats (0.8 ng/ml) relative to 0.5% Tween 80 dosed rats (0.5 ng/ml). At day 16 in the rat developing model, sirolimus, when given in phosal vehicle, produced an ED50 of 0.28 mg/ kg (i.e. inhibition of uninjected paw edema) that was about 5.5 times lower than using 0.5% Tween 80 as the suspending agent (ED50 = 1.6mg/kg). When combining sirolimus and CsA using precalculated doses for producing an additive effect in this adjuvant model, an additive inhibitory effect on uninjected paw edema was observed at equal combinational doses of 0.5 and 2 mg/kg, respectively. CONCLUSIONS: The phosal vehicle used in administering sirolimus increases the absorption and whole blood levels in the rat and the elevated blood levels correlated positively with the therapeutic effect in the rat developing AA model. In addition, combination therapy using sirolimus and CsA produced an additive effect in rat developing AA.

Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group.

OBJECTIVES: To evaluate the safety and physiologic response of inhaled nitric oxide (NO) in patients with acute respiratory distress syndrome (ARDS). In addition, the effect of various doses of inhaled NO on clinical outcome parameters was assessed. DESIGN: Prospective, multicenter, randomized, double-blind, placebo-controlled study. SETTING: Intensive care units of 30 academic, teaching, and community hospitals in the United States. PATIENTS: Patients with ARDS, as defined by the American-European Consensus Conference, were enrolled into the study if the onset of disease was within 72 hrs of randomization. INTERVENTIONS: Patients were randomized to receive placebo (nitrogen gas) or inhaled NO at concentrations of 1.25, 5, 20, 40, or 80 ppm. MEASUREMENTS AND MAIN RESULTS: Acute increases in PaO2, decreases in mean pulmonary arterial pressure, intensity of mechanical ventilation, and oxygenation index were examined. Clinical outcomes examined were the dose effects of inhaled NO on mortality, the number of days alive and off mechanical ventilation, and the number of days alive after meeting oxygenation criteria for extubation. A total of 177 patients were enrolled over a 14-month period. An acute response to treatment gas, defined as a PaO2 increase > or =20%, was seen in 60% of the patients receiving inhaled NO with no significant differences between dose groups. Twenty-four percent of placebo patients also had an acute response to treatment gas during the first 4 hrs. The initial increase in oxygenation translated into a reduction in the FIO2 over the first day and in the intensity of mechanical ventilation over the first 4 days of treatment, as measured by the oxygenation index. There were no differences among the pooled inhaled NO groups and placebo with respect to mortality rate, the number of days alive and off mechanical ventilation, or the number of days alive after meeting oxygenation criteria for extubation. However, patients receiving 5 ppm inhaled NO showed an improvement in these parameters. In this dose group, the percentage of patients alive and off mechanical ventilation at day 28 (a post hoc analysis) was higher (62% vs. 44%) than the placebo group. There was no apparent difference in the number or type of adverse events reported among those patients receiving inhaled NO compared with placebo. Four patients had methemoglobin concentrations >5%. The mean inspired nitrogen dioxide concentration in inhaled NO patients was 1.5 ppm. CONCLUSIONS: From this placebo-controlled study, inhaled NO appears to be well tolerated in the population of ARDS patients studied. With mechanical ventilation held constant, inhaled NO is associated with a significant improvement in oxygenation compared with placebo over the first 4 hrs of treatment. An improvement in oxygenation index was observed over the first 4 days. Larger phase III studies are needed to ascertain if these acute physiologic improvements can lead to altered clinical outcome.

Vasodilators in mechanical ventilation.

Vasodilators that affect the pulmonary vasculature are appealing adjuncts in many cardiopulmonary conditions that require mechanical ventilation such as ARDS, COPD, PPHN, and cardiothoracic surgery. The adverse systemic effects of parenteral PGE1 and parenteral prostacyclin limit their usefulness in critically ill patients. Liposomal PGE1 has few systemic effects, but thus far has not resulted in a significant clinical benefit in patients with ARDS. Inhaled NO and aerosolized prostacyclin offer the advantage of selective pulmonary vasodilation with minimal systemic effects. Both agents decrease PAP and in many clinical situations improve oxygenation; however, the physiologic effects of inhaled NO and aerosolized prostacyclin have not convincingly led to improved clinical outcomes. Currently, use of vasodilators in mechanically ventilated patients remains investigational.

Isolation and characterization of a diverse set of genes from carrot somatic embryos.

The early events in plant embryogenesis are critical for pattern formation, since it is during this process that the primary apical meristems and the embryo polarity axis are established. However, little is known about the molecular events that are unique to the early stages of embryogenesis. This study of gene expression during plant embryogenesis is focused on identifying molecular markers from carrot (Daucus carota) somatic embryos and characterizing the expression and regulation of these genes through embryo development. A cDNA library, prepared from polysomal mRNA of globular embryos, was screened using a subtracted probe; 49 clones were isolated and preliminarily characterized. Sequence analysis revealed a large set of genes, including many new genes, that are expressed in a variety of patterns during embryogenesis and may be regulated by different molecular mechanisms. To our knowledge, this group of clones represents the largest collection of embryo-enhanced genes isolated thus far, and demonstrates the utility of the subtracted-probe approach to the somatic embryo system. It is anticipated that many of these genes may serve as useful molecular markers for early embryo development.

Blood gas monitoring.

Arterial blood gas (ABG) measurements are one of the most frequently requested laboratory examinations in critically ill patients. ABGs include measurement of pHa, PaCO2, PaO2, and oxyhemoglobin saturation. These measurements allow for assessment of the nature, progression, and severity of metabolic and respiratory disturbances.

The electronic window to the world.

Computer networking is a fundamental change in communication technology that carries with it the same significance as the development of human language. The discovery of new tools adds to the human experience, but the ability to communicate and share that knowledge and wisdom results in a factorial increase in the collective wisdom of a global community. This paper presents a brief history and overview of the Internet and then discusses how network application tools can be used in dentistry. Examples of various implementations will be given and a brief discussion of some constraints to implementation of network technology is also included.