The Reviewer Academy of the Society of Critical Care Medicine: Key Principles and Strategic Plan.

The Society of Critical Care Medicine (SCCM) Reviewer Academy seeks to train and establish a community of trusted, reliable, and skilled peer reviewers with diverse backgrounds and interests to promote high-quality reviews for each of the SCCM journals. Goals of the Academy include building accessible resources to highlight qualities of excellent manuscript reviews; educating and mentoring a diverse group of healthcare professionals; and establishing and upholding standards for insightful and informative reviews. This manuscript will map the mission of the Reviewer Academy with a succinct summary of the importance of peer review, process of reviewing a manuscript, and the expected ethical standards of reviewers. We will equip readers to target concise, thoughtful feedback as peer reviewers, advance their understanding of the editorial process and inspire readers to integrate medical journalism into diverse professional careers.

The Association of Increasing Hospice Use With Decreasing Hospital Mortality: An Analysis of the National Inpatient Sample.

EXECUTIVE SUMMARY: Usage of hospice services for patients facing life-limiting illness has steadily increased. In these services, hospitals discharge patients to various hospice settings, including the inpatient model, where a patient may remain in the discharging hospital to receive hospice services. In this discharge practice, the patient is considered a hospital survivor and subsequent hospice death. The purpose of the study was to determine if the decline of in-hospital mortality for six common high-volume admission diagnoses could be attributed in part to an increase in discharges to a hospice setting for end-of-life care. In this retrospective study using the National Inpatient Sample database from 2007 to 2011, we identified patients ≥18 years for six acute and chronic diagnoses: heart failure, chronic obstructive pulmonary disease, acute myocardial infarction, acute myocardial infarction with cardiogenic shock, septic shock, and lung neoplasm (cancer). We categorized patients according to their hospital discharge disposition as hospice or in-hospital mortality. A total of 10,458,728 patients met our criteria, of which 2.72% were discharged to hospice and 6.38% died. Compared to patients who died in the hospital, hospice patients were older, had a shorter length of stay, and experienced more comorbidities. Hospice use was more common in Medicare patients, in nonteaching hospitals, and in the South. White individuals were more likely to be discharged to hospice compared to nonwhites. Among the six selected diagnoses over the 5-year period, hospice use rose as observed mortality decreased. Our findings suggest that variability among hospitals in hospice use will affect benchmarked hospital mortality comparisons and could inappropriately reward or penalize hospitals in their public reporting.

Electrolyte Disturbances in Critically Ill Cancer Patients: An Endocrine Perspective.

Electrolyte disturbances are frequently encountered in critically ill oncology patients. Hyponatremia and hypernatremia as well as hypocalcemia and hypercalcemia are among the most commonly encountered electrolyte abnormalities. In the intensive care unit, management of critical electrolyte disturbances is focused on initial evaluation and immediate treatment plan to prevent severe complications. A PubMed search was performed to identify best available evidence for evaluation and management of dysnatremias, hypocalcemia, and hypercalcemia. Current literature was reviewed regarding the management of electrolyte disturbances. The role of new therapeutic options, for example, vaptans for hyponatremia, teriparatide for hypocalcemia, and denosumab for hypercalcemia, is discussed. Early diagnosis and appropriate management are expected to reduce adverse outcomes.

Effect of Targeted Polymyxin B Hemoperfusion on 28-Day Mortality in Patients With Septic Shock and Elevated Endotoxin Level: The EUPHRATES Randomized Clinical Trial.

Importance: Polymyxin B hemoperfusion reduces blood endotoxin levels in sepsis. Endotoxin activity can be measured in blood with a rapid assay. Treating patients with septic shock and elevated endotoxin activity using polymyxin B hemoperfusion may improve clinical outcomes. Objective: To test whether adding polymyxin B hemoperfusion to conventional medical therapy improves survival compared with conventional therapy alone among patients with septic shock and high endotoxin activity. Design, Setting, and Participants: Multicenter, randomized clinical trial involving 450 adult critically ill patients with septic shock and an endotoxin activity assay level of 0.60 or higher enrolled between September 2010 and June 2016 at 55 tertiary hospitals in North America. Last follow-up was June 2017. Interventions: Two polymyxin B hemoperfusion treatments (90-120 minutes) plus standard therapy completed within 24 hours of enrollment (n = 224 patients) or sham hemoperfusion plus standard therapy (n = 226 patients). Main Outcomes and Measures: The primary outcome was mortality at 28 days among all patients randomized (all participants) and among patients randomized with a multiple organ dysfunction score (MODS) of more than 9. Results: Among 450 eligible enrolled patients (mean age, 59.8 years; 177 [39.3%] women; mean APACHE II score 29.4 [range, 0-71 with higher scores indicating greater severity), 449 (99.8%) completed the study. Polymyxin B hemoperfusion was not associated with a significant difference in mortality at 28 days among all participants (treatment group, 84 of 223 [37.7%] vs sham group 78 of 226 [34.5%]; risk difference [RD], 3.2%; 95% CI, -5.7% to 12.0%; relative risk [RR], 1.09; 95% CI, 0.85-1.39; P = .49) or in the population with a MODS of more than 9 (treatment group, 65 of 146 [44.5%] vs sham, 65 of 148 [43.9%]; RD, 0.6%; 95% CI, -10.8% to 11.9%; RR, 1.01; 95% CI, 0.78-1.31; P = .92). Overall, 264 serious adverse events were reported (65.1% treatment group vs 57.3% sham group). The most frequent serious adverse events were worsening of sepsis (10.8% treatment group vs 9.1% sham group) and worsening of septic shock (6.6% treatment group vs 7.7% sham group). Conclusions and Relevance: Among patients with septic shock and high endotoxin activity, polymyxin B hemoperfusion treatment plus conventional medical therapy compared with sham treatment plus conventional medical therapy did not reduce mortality at 28 days. Trial Registration: ClinicalTrials.gov Identifier: NCT01046669.

Talactoferrin in Severe Sepsis: Results From the Phase II/III Oral tAlactoferrin in Severe sepsIS Trial.

OBJECTIVE: Talactoferrin alfa is a recombinant form of the human glycoprotein, lactoferrin, which has been shown to have a wide range of effects on the immune system. This phase II/III clinical trial compared talactoferrin with placebo, in addition to standard of care, in patients with severe sepsis. DESIGN: Multicenter, randomized, placebo-controlled, phase II/III clinical study. SETTING: Seventy-seven centers in 10 countries. PATIENTS: Adult (> 18 yr) patients admitted to one of the participating centers with severe sepsis who were receiving antimicrobial therapy and able to take liquid medication by mouth or feeding tube. INTERVENTIONS: Patients were randomized to receive either talactoferrin (1.5 g, 15 mL) or placebo three times a day orally or by another enteral route for 28 days or until ICU discharge. MEASUREMENTS AND MAIN RESULTS: The study was terminated after 305 patients had been enrolled (153 talactoferrin and 152 placebo) because of futility and safety concerns identified by the Data Safety Monitoring Board. There were no significant differences between groups in baseline characteristics including age, sex, site of infection, and severity scores. Twenty-eight-day mortality was higher in talactoferrin-treated patients although this difference was not statistically significant (24.8% vs 17.8% placebo; p = 0.117). The difference was largely the result of differences in patients with shock (talactoferrin, 33/105 [31.4%] vs placebo, 21/104 [20.2%]; p = 0.064); no mortality difference was seen in patients without shock (talactoferrin, 5/48 [10.4%] vs placebo, 6/48 [12.5%]; p = 0.806). In-hospital (43/153 [28.1%] vs 27/152 [17.8%]; p = 0.037) and 3-month (46/153 [30.1%] vs 31/152 [20.4%]; p = 0.036) mortality rates were significantly higher in talactoferrin-treated patients than in patients in the placebo group. The occurrence of treatment-related adverse or serious adverse events was similar between groups. CONCLUSIONS: Administration of oral talactoferrin was not associated with reduced 28-day mortality in patients with severe sepsis and may even be harmful.

Lactate measurements in sepsis-induced tissue hypoperfusion: results from the Surviving Sepsis Campaign database.

OBJECTIVE: The Surviving Sepsis Campaign guidelines recommend obtaining a serum lactate measurement within 6 hours of presentation for all patients with suspected severe sepsis or septic shock. A lactate greater than 4 mmol/L qualifies for administration of early quantitative resuscitation therapy. We evaluated lactate elevation (with special attention to values > 4 mmol/L) and presence or absence of hypotension as a marker of clinical outcome. DESIGN AND SETTING: The Surviving Sepsis Campaign developed a database to assess the overall effect of the sepsis bundles as a performance improvement tool for clinical practice and patient outcome. This analysis focuses on one element of the Surviving Sepsis Campaign's resuscitation bundle, measuring serum lactate in adult severe sepsis or septic shock patients and its interaction with hypotension. This analysis was conducted on data submitted from January 2005 through March 2010. SUBJECTS: Data from 28,150 subjects at 218 sites were analyzed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Unadjusted analysis of the 28,150 observations from the Surviving Sepsis Campaign database demonstrated a significant mortality increase with the presence of hypotension in conjunction with serum lactate elevation greater than 2 mmol/L. On multivariable analysis, only lactate values greater than 4 mmol/L, in conjunction with hypotension, significantly increased mortality when compared with the referent group of lactate values less than 2 mmol/L and not hypotensive. Mortality was 44.5% in patients with combined lactate greater than 4 mmol/L and hypotension when compared with 29% mortality in patients not meeting either criteria. CONCLUSIONS: Serum lactate was commonly measured within 6 hours of presentation in the management of severe sepsis or septic shock in this subset analysis of the Surviving Sepsis Campaign database in accordance with the Surviving Sepsis Campaign guidelines. Our results demonstrate that elevated lactate levels are highly associated with in-hospital mortality. However, only patients who presented with lactate values greater than 4 mmol/L, with and without hypotension, are significantly associated with in-hospital mortality and is associated with a significantly higher risk than intermediate levels (2-3 and 3-4 mmol/L). This supports the use of the cutoff of greater than 4 mmol/L as a qualifier for future clinical trials in severe sepsis or septic shock in patient populations who use quantitative resuscitation and the Surviving Sepsis Campaign bundles as standard of care.

Surviving Sepsis Campaign: association between performance metrics and outcomes in a 7.5-year study.

PURPOSE: To determine the association between compliance with the Surviving Sepsis Campaign (SSC) performance bundles and mortality. DESIGN: Compliance with the SSC performance bundles, which are based on the 2004 SSC guidelines, was measured in 29,470 subjects entered into the SSC database from January 1, 2005, through June 30, 2012. Compliance was defined as evidence that all bundle elements were achieved. SETTING: Two hundred eighteen community, academic, and tertiary care hospitals in the United States, South America, and Europe. PATIENTS: Patients from the emergency department, medical and surgical wards, and ICU who met diagnosis criteria for severe sepsis and septic shock. METHODS: A multifaceted, collaborative change intervention aimed at facilitating adoption of the SSC resuscitation and management bundles was introduced. Compliance with the SSC bundles and associated mortality rate was the primary outcome variable. RESULTS: Overall lower mortality was observed in high (29.0%) versus low (38.6%) resuscitation bundle compliance sites (p < 0.001) and between high (33.4%) and low (32.3%) management bundle compliance sites (p = 0.039). Hospital mortality rates dropped 0.7% per site for every three months (quarter) of participation (p < 0.001). Hospital and intensive care unit length of stay decreased 4% (95% CI: 1% - 7%; p = 0.012) for every 10% increase in site compliance with the resuscitation bundle. CONCLUSIONS: This analysis demonstrates that increased compliance with sepsis performance bundles was associated with a 25% relative risk reduction in mortality rate. Every 10% increase in compliance and additional quarter of participation in the SSC initiative was associated with a significant decrease in the odds ratio for hospital mortality. These results demonstrate that performance metrics can drive change in clinical behavior, improve quality of care, and may decrease mortality in patients with severe sepsis and septic shock.

Brain injury as a risk factor for fever upon admission to the intensive care unit and association with in-hospital case fatality: a matched cohort study.

PURPOSE: To test the hypothesis that fever was more frequent in critically ill patients with brain injury when compared to nonneurological patients and to study its effect on in-hospital case fatality. METHODS: Retrospective matched cohort study utilizing a single-center prospectively compiled registry. Critically ill neurological patients ≥18 years and consecutively admitted to the intensive care unit (ICU) with acute ischemic stroke (AIS), intracerebral hemorrhage (ICH), and traumatic brain injury (TBI) were selected. Patients were matched by sex, age, and Acute Physiology and Chronic Health Evaluation II (APACHE-II) to a cohort of nonneurological patients. Fever was defined as any temperature ≥37.5°C within the first 24 hours upon admission to the ICU. The primary outcome measure was in-hospital case fatality. RESULTS: Mean age among neurological patients was 65.6 ± 15 years, 46% were men, and median APACHE-II was 15 (interquartile range 11-20). There were 18% AIS, 27% ICH, and 6% TBI. More neurological patients experienced fever than nonneurological patients (59% vs 47%, P = .007). The mean hospital length of stay was higher for nonneurological patients (18 ± 20 vs 14 ± 15 days, P = .007), and more neurological patients were dead at hospital discharge (29% vs 20%, P < .0001). After risk factor adjustment, diagnosis (neurological vs nonneurological), and the probability of being exposed to fever (propensity score), the following variables were associated with higher in-hospital case fatality: APACHE-II, neurological diagnosis, mean arterial pressure, cardiovascular and respiratory dysfunction in ICU, and fever (odds ratio 1.9, 95% confidence interval 1.04-3.6, P = .04). CONCLUSION: These data suggest that fever is a frequent occurrence after brain injury, and that it is independently associated with in-hospital case fatality.

The next generation of sepsis clinical trial designs: what is next after the demise of recombinant human activated protein C?*.

OBJECTIVE: The developmental pipeline for novel therapeutics to treat sepsis has diminished to a trickle compared to previous years of sepsis research. While enormous strides have been made in understanding the basic molecular mechanisms that underlie the pathophysiology of sepsis, a long list of novel agents have now been tested in clinical trials without a single immunomodulating therapy showing consistent benefit. The only antisepsis agent to successfully complete a phase III clinical trial was human recumbent activated protein C. This drug was taken off the market after a follow-up placebo-controlled trial (human recombinant activated Protein C Worldwide Evaluation of Severe Sepsis and septic Shock [PROWESS SHOCK]) failed to replicate the favorable results of the initial registration trial performed ten years earlier. We must critically reevaluate our basic approach to the preclinical and clinical evaluation of new sepsis therapies. DATA SOURCES: We selected the major clinical studies that investigated interventional trials with novel therapies to treat sepsis over the last 30 years. STUDY SELECTION: Phase II and phase III trials investigating new treatments for sepsis and editorials and critiques of these studies. DATA EXTRACTION: Selected manuscripts and clinical study reports were analyzed from sepsis trials. Specific shortcomings and potential pit falls in preclinical evaluation and clinical study design and analysis were reviewed and synthesized. DATA SYNTHESIS: After review and discussion, a series of 12 recommendations were generated with suggestions to guide future studies with new treatments for sepsis. CONCLUSIONS: We need to improve our ability to define appropriate molecular targets for preclinical development and develop better methods to determine the clinical value of novel sepsis agents. Clinical trials must have realistic sample sizes and meaningful endpoints. Biomarker-driven studies should be considered to categorize specific "at risk" populations most likely to benefit from a new treatment. Innovations in clinical trial design such as parallel crossover design, alternative endpoints, or adaptive trials should be pursued to improve the outlook for future interventional trials in sepsis.

Sepsis severity score: an internationally derived scoring system from the surviving sepsis campaign database*.

OBJECTIVE: As the Surviving Sepsis Campaign was assessing patient-level data over multiple countries, we sought to evaluate the use of a pragmatic and parsimonious severity-of-illness scoring system for patients with sepsis in an attempt to provide appropriate comparisons with practical application. DESIGN: Prospective, observational evaluation. PATIENTS: Data from 23,438 patients with suspected or confirmed sepsis from 218 hospitals in 18 countries were evaluated. SETTING: This analysis was conducted on prospective data submitted to a database from January 2005 through March 2010. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Maximum likelihood logistic regression was used to estimate model coefficients, and these were then used to develop a Sepsis Severity Score. The probability of hospital mortality was estimated using the Sepsis Severity Score as the sole variable in a logistic regression model. Univariable logistic regression determined which variables were included in the multivariable predictor model. The scale of continuous variables was assessed using fractional polynomials. Two-way interactions between variables were considered for model inclusion if the interaction p value is less than 0.05. The prediction model was developed based on randomly selecting 90% of available patients and was validated on the remaining 10%, as well as by using a bootstrapping technique. The p values for the Hosmer-Lemeshow goodnessof-fit statistic in the developmental and validation datasets were considerably greater than 0.05, suggesting good calibration. Development and validation areas under the receiver operator curve curves were 0.736 and 0.748, respectively. Observed and estimated probabilities of hospital mortality for the total population were both 0.334. The validation and the developmental datasets were gradually compared over deciles of predicted mortality and found to be very similar. CONCLUSION: The Sepsis Severity Score accurately estimated the probability of hospital mortality in severe sepsis and septic shock patients. It performed well with respect to calibration and discrimination, which remained consistent over deciles. It functioned well over international geographic regions. This robust, population-specific evaluation of international severe sepsis patients provides an effective and accurate mortality estimate allowing for appropriate quality comparisons with practical clinical and research application.

Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program.

OBJECTIVES: Compelling evidence has shown that aggressive resuscitation bundles, adequate source control, appropriate antibiotic therapy, and organ support are cornerstone for the success in the treatment of patients with sepsis. Delay in the initiation of appropriate antibiotic therapy has been recognized as a risk factor for mortality. To perform a retrospective analysis on the Surviving Sepsis Campaign database to evaluate the relationship between timing of antibiotic administration and mortality. DESIGN: Retrospective analysis of a large dataset collected prospectively for the Surviving Sepsis Campaign. SETTING: One hundred sixty-five ICUs in Europe, the United States, and South America. PATIENTS: A total of 28,150 patients with severe sepsis and septic shock, from January 2005 through February 2010, were evaluated. INTERVENTIONS: Antibiotic administration and hospital mortality. MEASUREMENTS AND MAIN RESULTS: A total of 17,990 patients received antibiotics after sepsis identification and were included in the analysis. In-hospital mortality was 29.7% for the cohort as a whole. There was a statically significant increase in the probability of death associated with the number of hours of delay for first antibiotic administration. Hospital mortality adjusted for severity (sepsis severity score), ICU admission source (emergency department, ward, vs ICU), and geographic region increased steadily after 1 hour of time to antibiotic administration. Results were similar in patients with severe sepsis and septic shock, regardless of the number of organ failure. CONCLUSIONS: The results of the analysis of this large population of patients with severe sepsis and septic shock demonstrate that delay in first antibiotic administration was associated with increased in-hospital mortality. In addition, there was a linear increase in the risk of mortality for each hour delay in antibiotic administration. These results underscore the importance of early identification and treatment of septic patients in the hospital setting.