Christoph Engel

Intensive Insulin Therapy and Pentastarch Resuscitation in Severe Sepsis

BACKGROUND The role of intensive insulin therapy in patients with severe sepsis is uncertain. Fluid resuscitation improves survival among patients with septic shock, but evidence is lacking to support the choice of either crystalloids or colloids. METHODS In a multicenter, two-by-two factorial trial, we randomly assigned patients with severe sepsis to receive either intensive insulin therapy to maintain euglycemia or conventional insulin therapy and either 10% pentastarch, a low-molecular-weight hydroxyethyl starch (HES 200/0.5), or modified Ringers lactate for fluid resuscitation. The rate of death at 28 days and the mean score for organ failure were coprimary end points. RESULTS The trial was stopped early for safety reasons. Among 537 patients who could be evaluated, the mean morning blood glucose level was lower in the intensive-therapy group (112 mg per deciliter [6.2 mmol per liter]) than in the conventional-therapy group (151 mg per deciliter [8.4 mmol per liter], P<0.001). However, at 28 days, there was no significant difference between the two groups in the rate of death or the mean score for organ failure. The rate of severe hypoglycemia (glucose level, < or = 40 mg per deciliter [2.2 mmol per liter]) was higher in the intensive-therapy group than in the conventional-therapy group (17.0% vs. 4.1%, P<0.001), as was the rate of serious adverse events (10.9% vs. 5.2%, P=0.01). HES therapy was associated with higher rates of acute renal failure and renal-replacement therapy than was Ringers lactate. CONCLUSIONS The use of intensive insulin therapy placed critically ill patients with sepsis at increased risk for serious adverse events related to hypoglycemia. As used in this study, HES was harmful, and its toxicity increased with accumulating doses. (ClinicalTrials.gov number, NCT00135473.)

Effect of Empirical Treatment With Moxifloxacin and Meropenem vs Meropenem on Sepsis-Related Organ Dysfunction in Patients With Severe Sepsis: A Randomized Trial

CONTEXT Early appropriate antimicrobial therapy leads to lower mortality rates associated with severe sepsis. The role of empirical combination therapy comprising at least 2 antibiotics of different mechanisms remains controversial. OBJECTIVE To compare the effect of moxifloxacin and meropenem with the effect of meropenem alone on sepsis-related organ dysfunction. DESIGN, SETTING, AND PATIENTS A randomized, open-label, parallel-group trial of 600 patients who fulfilled criteria for severe sepsis or septic shock (n = 298 for monotherapy and n = 302 for combination therapy). The trial was performed at 44 intensive care units in Germany from October 16, 2007, to March 23, 2010. The number of evaluable patients was 273 in the monotherapy group and 278 in the combination therapy group. INTERVENTIONS Intravenous meropenem (1 g every 8 hours) and moxifloxacin (400 mg every 24 hours) or meropenem alone. The intervention was recommended for 7 days and up to a maximum of 14 days after randomization or until discharge from the intensive care unit or death, whichever occurred first. MAIN OUTCOME MEASURE Degree of organ failure (mean of daily total Sequential Organ Failure Assessment [SOFA] scores over 14 days; score range: 0-24 points with higher scores indicating worse organ failure); secondary outcome: 28-day and 90-day all-cause mortality. Survivors were followed up for 90 days. RESULTS Among 551 evaluable patients, there was no statistically significant difference in mean SOFA score between the meropenem and moxifloxacin group (8.3 points; 95% CI, 7.8-8.8 points) and the meropenem alone group (7.9 points; 95% CI, 7.5-8.4 points) (P = .36). The rates for 28-day and 90-day mortality also were not statistically significantly different. By day 28, there were 66 deaths (23.9%; 95% CI, 19.0%-29.4%) in the combination therapy group compared with 59 deaths (21.9%; 95% CI, 17.1%-27.4%) in the monotherapy group (P = .58). By day 90, there were 96 deaths (35.3%; 95% CI, 29.6%-41.3%) in the combination therapy group compared with 84 deaths (32.1%; 95% CI, 26.5%-38.1%) in the monotherapy group (P = .43). CONCLUSION Among adult patients with severe sepsis, treatment with combined meropenem and moxifloxacin compared with meropenem alone did not result in less organ failure. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00534287.

Clumsy Solutions for a Complex World

Successful solutions to pressing social ills tend to consist of innovative combinations of a limited set of alternative ways of perceiving and resolving the issues. These contending policy perspectives justify, represent and stem from four different ways of organizing social relations: hierarchy, individualism, egalitarianism and fatalism. Each of these perspectives: (1) distils certain elements of experience and wisdom that are missed by the others; (2) provides a clear expression of the way in which a significant portion of the populace feels we should live with one another and with nature; and (3) needs all of the others in order to be sustainable. ‘Clumsy solutions’– policies that creatively combine all opposing perspectives on what the problems are and how they should be resolved – are therefore called for. We illustrate these claims for the issue of global warming.

Practice and perception—A nationwide survey of therapy habits in sepsis*

Objective:To simultaneously determine perceived vs. practiced adherence to recommended interventions for the treatment of severe sepsis or septic shock. Design:One-day cross-sectional survey. Setting:Representative sample of German intensive care units stratified by hospital size. Patients:Adult patients with severe sepsis or septic shock. Interventions:None. Measurements and Main Results:Practice recommendations were selected by German Sepsis Competence Network (SepNet) investigators. External intensivists visited intensive care units randomly chosen and asked the responsible intensive care unit director how often these recommendations were used. Responses “always” and “frequently” were combined to depict perceived adherence. Thereafter patient files were audited. Three hundred sixty-six patients on 214 intensive care units fulfilled the criteria and received full support. One hundred fifty-two patients had acute lung injury or acute respiratory distress syndrome. Low-tidal volume ventilation ≤6 mL/kg/predicted body weight was documented in 2.6% of these patients. A total of 17.1% patients had tidal volume between 6 and 8 mL/kg predicted body weight and 80.3% >8 mL/kg predicted body weight. Mean tidal volume was 10.0 ± 2.4 mL/kg predicted body weight. Perceived adherence to low-tidal volume ventilation was 79.9%. Euglycemia (4.4–6.1 mmol/L) was documented in 6.2% of 355 patients. A total of 33.8% of patients had blood glucose levels ≤8.3 mmol/L and 66.2% were hyperglycemic (blood glucose >8.3 mmol/L). Among 207 patients receiving insulin therapy, 1.9% were euglycemic, 20.8% had blood glucose levels ≤8.3 mmol/L, and 1.0% were hypoglycemic. Overall, mean maximal glucose level was 10.0 ± 3.6 mmol/L. Perceived adherence to strict glycemic control was 65.9%. Although perceived adherence to recommendations was higher in academic and larger hospitals, actual practice was not significantly influenced by hospital size or university affiliation. Conclusions:This representative survey shows that current therapy of severe sepsis in German intensive care units complies poorly with practice recommendations. Intensive care unit directors perceive adherence to be higher than it actually is. Implementation strategies involving all intensive care unit staff are needed to overcome this gap between current evidence-based knowledge, practice, and perception.

Current practice in nutritional support and its association with mortality in septic patients--results from a national, prospective, multicenter study.

Objective:To identify current clinical practice regarding nutrition and its association with morbidity and mortality in patients with severe sepsis or septic shock in Germany. Design:Nationwide prospective, observational, cross-sectional, 1-day point-prevalence study. Setting:The study included 454 intensive care units from a representative sample of 310 hospitals stratified by size. Patients:Participants were 415 patients with severe sepsis or septic shock (according to criteria of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference). Interventions:None. Measurements and Main Results:Data were collected by on-site audits of trained external study physicians during randomly scheduled visits during 1 yr. Valid data on nutrition were available for 399 of 415 patients. The data showed that 20.1% of patients received exclusively enteral nutrition, 35.1% exclusively parenteral nutrition, and 34.6% mixed nutrition (parenteral and enteral); 10.3% were not fed at all. Patients with gastrointestinal/intra-abdominal infection, pancreatitis or neoplasm of the gastrointestinal tract, mechanical ventilation, or septic shock were less likely to receive exclusively enteral nutrition. Median Acute Physiology and Chronic Health Evaluation II and Sepsis-related Organ Failure Assessment scores were significantly different among the nutrition groups. Overall hospital mortality was 55.2%. Hospital mortality was significantly higher in patients receiving exclusively parenteral (62.3%) or mixed nutrition (57.1%) than in patients with exclusively enteral nutrition (38.9%) (p = .005). After adjustment for patient morbidity (Acute Physiology and Chronic Health Evaluation II score, presence of septic shock) and treatment factors (mechanical ventilation), multivariate analysis revealed that the presence of parenteral nutrition was significantly predictive of mortality (odds ratio, 2.09; 95% confidence interval, 1.29–3.37). Conclusions:Patients with severe sepsis or septic shock in German intensive care units received preferentially parenteral or mixed nutrition. The use of parenteral nutrition was associated with an increased risk of death.

How Much Collusion? A Meta-Analysis on Oligopoly Experiments

Oligopoly has been among the first topics in experimental economics. Over half a century, some 150 papers have been published. Each individual paper was interested in demonstrating one effect, but in order to do so, experimenters had to specify many more parameters. Thus they have generated a huge body of evidence, untapped so far. This meta-analysis makes this evidence available. More than 100 of the papers lend themselves to calculating an index of collusion. The database behind this paper covers some 500 different settings. The experimental results may be normalized as a percentage of the span between the Walrasian and the Pareto outcomes. In the same way, results may be expressed as a percentage of the distance between the Nash and the Pareto outcomes. For each and every one of the parameters, these two indices make it possible to answer two questions: How far is the market outcome away from the competitive equilibrium? And how good is the Nash prediction? Most importantly, however, the meta-analysis sheds light on how features of the experimental setting interact with each other. Most main effects and many interaction effects are indeed statistically significant.

Automatic Control of Pressure Support for Ventilator Weaning in Surgical Intensive Care Patients

RATIONALE Despite its ability to reduce overall ventilation time, protocol-guided weaning from mechanical ventilation is not routinely used in daily clinical practice. Clinical implementation of weaning protocols could be facilitated by integration of knowledge-based, closed-loop controlled protocols into respirators. OBJECTIVES To determine whether automated weaning decreases overall ventilation time compared with weaning based on a standardized written protocol in an unselected surgical patient population. METHODS In this prospective controlled trial patients ventilated for longer than 9 hours were randomly allocated to receive either weaning with automatic control of pressure support ventilation (automated-weaning group) or weaning based on a standardized written protocol (control group) using the same ventilation mode. The primary end point of the study was overall ventilation time. MEASUREMENTS AND MAIN RESULTS Overall ventilation time (median [25th and 75th percentile]) did not significantly differ between the automated-weaning (31 [19-101] h; n = 150) and control groups (39 [20-118] h; n = 150; P = 0.178). Patients who underwent cardiac surgery (n = 132) exhibited significantly shorter overall ventilation times in the automated-weaning (24 [18-57] h) than in the control group (35 [20-93] h; P = 0.035). The automated-weaning group exhibited shorter ventilation times until the first spontaneous breathing trial (1 [0-15] vs. 9 [1-51] h; P = 0.001) and a trend toward fewer tracheostomies (17 vs. 28; P = 0.075). CONCLUSIONS Overall ventilation times did not significantly differ between weaning using automatic control of pressure support ventilation and weaning based on a standardized written protocol. Patients after cardiac surgery may benefit from automated weaning. Implementation of additional control variables besides the level of pressure support may further improve automated-weaning systems. Clinical trial registered with www.clinicaltrials.gov (NCT 00445289).

The Case for Clumsiness

Most climatologists agree that by burning fossil fuels and engaging in other forms of consumption and production we are increasing the amount of greenhouse gases that float around in the atmosphere. These gases, in trapping some of the sun’s heat, warm the earth and enable life. The trouble is, some predict, that if we continue to accumulate those gases, over the course of the new century the average temperature on earth will rise and local climates will change, with possibly catastrophic consequences. Will this indeed happen? Does climate-change put the future of the world at risk? Can only a radical reallocation of global wealth and power rescue us from this threat? Or should people not be overly worried, as the steady march of technological progress will see us through in the end?

The Behaviour of Corporate Actors. A Survey of the Empirical Literature

Much of socially relevant behaviour does not originate in isolated individuals. It is embedded in institutional arrangements. Embeddedness can be so pronounced that outsiders no longer focus on judgement and decision making of individuals contributing to the course of action. Instead they ascribe the behaviour to the institution, to which they refer as a corporate actor. This social practice makes it meaningful to compare isolated individuals and corporate actors on the same tasks. This paper surveys the empirical literature on the question from experimental economics, social psychology, and organisation science.

We are Not Alone: The Impact of Externalities on Public Good Provision

Public good provision is often local and also affects bystanders. Is provision harder if contributions harm bystanders, and is provision easier if outsiders gain a windfall profit? In an experiment we observe that both positive and negative externalities reduce provision levels whenever actors risk falling back behind bystanders. The mere presence of unaffected bystanders already dampens contributions. This behavior seems to result from the interplay of two motives: the desire to realize opportunities for joint gains, and concerns for comparative performance. Individual payoff comparisons to the other actors as well as to individual bystanders drive contributions down.