Recent Research

Summaries from ACP Hospitalist Weekly.

Risk factors known during critical care admission linked to long-term mortality after sepsis

Patient- and sepsis-specific risk factors available at admission for sepsis could help identify which sepsis survivors are at the highest risk of mortality up to six years after discharge, a recent study found.

The cohort study included a sample of 94,748 adults (mean age, 61.3 years; 46.0% women; 90.8% white) who survived to hospital discharge following an admission for sepsis (according to Sepsis-3 criteria) at 192 critical care units in England. Participants were identified from consecutive critical care admissions between April 1, 2009, and March 31, 2014, with survival status ascertained as of March 31, 2015.

Researchers assessed the association between long-term mortality and risk factors that were known during the index admission for sepsis, including both generic patient characteristics (age, sex, race/ethnicity, severe comorbidities, prehospitalization dependency, surgical status, and acute illness severity) and sepsis-specific patient characteristics (site of infection, number of organ dysfunctions, and septic shock status). Results were published May 31 by JAMA Network Open.

By one year after discharge, 15% of sepsis survivors had died, with 6% to 8% dying each year over the next five years. Older age, male sex, presence of one or more severe comorbidities, prehospitalization dependency, and nonsurgical (medical) status increased the risk of long-term mortality. The most common site of infection was respiratory, present in 46.3% of patients. Compared with respiratory site of infection, gastrointestinal, genitourinary, musculoskeletal, and neurological sites of infection had adjusted hazard ratios for long-term mortality that were less than 1.

Compared with single-organ dysfunction, having two or three (but not four or more) organ dysfunctions was associated with increased risk of long-term mortality (adjusted hazard ratios, 1.07 [95% CI, 1.01 to 1.13] and 1.18 [95% CI, 1.03 to 1.14], respectively). A patient's Acute Physiology and Chronic Health Evaluation acute physiology component score had an incremental association with long-term mortality (adjusted hazard ratio, 1.11 for every five-point increase [95% CI, 1.08 to 1.13]). Septic shock at admission had an adjusted hazard ratio of 0.89 (95% CI, 0.85 to 0.92; P<0.001).

Limitations of the study include differences in follow-up duration and the fact that the cohort did not include patients who were admitted to critical care for other reasons and developed sepsis more than 24 hours into their stay, the study authors noted. “Our research provides validity to target sepsis survivor populations based on index admission characteristics, for biological characterization and designing interventions to reduce long-term mortality,” they concluded.

Glucocorticoids associated with increased infection risk after joint replacement in patients with RA

Glucocorticoid use, especially doses greater than 10 mg/d, was associated with higher risk for adverse events among patients with rheumatoid arthritis undergoing joint replacement surgery, while risk for infection requiring hospitalization, prosthetic joint infection, and readmission were similar across biologics, a study found.

To compare risk for postoperative infection among biologics and to evaluate the risk associated with glucocorticoids, researchers conducted a retrospective cohort study of Medicare and private administrative data from January 2006 through September 2015 among adults with rheumatoid arthritis who were having elective inpatient total knee or hip arthroplasty, either primary or revision, and had a recent infusion of or prescription for abatacept, adalimumab, etanercept, infliximab, rituximab, or tocilizumab before surgery. The primary outcomes were infection requiring hospitalization within 30 days of surgery (described as hospitalized infection) and prosthetic joint infection within a year.

Image by Getty Images
Image by Getty Images

The study was funded by the Rheumatology Research Foundation, National Institutes of Health, and Bristol-Myers Squibb. Results were published online on May 21 by Annals of Internal Medicine and appeared in the June 18 issue.

Among 9,911 patients treated with biologics, 10,923 surgical procedures were identified. Rates of 30-day readmission and serious postoperative infection were similar among biologics. Compared with an 8.16% risk for hospitalized infection with abatacept, predicted risk from propensity-weighted models ranged from 6.87% (95% CI, 5.30% to 8.90%) with adalimumab to 8.90% (95% CI, 5.70% to 13.52%) with rituximab. Compared with a 2.14% one-year cumulative incidence of prosthetic joint infection with abatacept, predicted incidence ranged from 0.35% (95% CI, 0.11% to 1.12%) with rituximab to 3.67% (95% CI, 1.69% to 7.88%) with tocilizumab.

In contrast, glucocorticoids were associated with a dose-dependent increase in the risk for adverse outcomes, with greater risk even with modest doses. Compared to no glucocorticoid use, use of more than 10 mg/d resulted in a predicted risk for hospitalized infection of 13.25% (95% CI, 9.72% to 17.81%) versus 6.78% and a predicted one-year cumulative incidence of prosthetic joint infection of 3.83% (95% CI, 2.13% to 6.87%) versus 2.09%.

“Glucocorticoid use is strongly associated with postoperative infection risk even at modest doses. Minimizing glucocorticoid exposure before surgery should be a primary focus of perioperative medication management,” the study authors wrote. They added that limitations include a possibility of residual confounding and small sample sizes for rituximab and tocilizumab.

An accompanying editorial noted that the study does not resolve the question of whether withholding biologic therapies in the perioperative period reduces patients' overall risk for infection complications.

“Instead, it provides compelling evidence, once again, of the substantial risk for serious postoperative infections associated with glucocorticoid use. There is a critical need for research to elucidate the risks and benefits of withholding biologics to optimize patient outcomes,” the editorial concluded.

Eosinophil-guided therapy appears noninferior to standard care for COPD exacerbations

Eosinophil-guided therapy was noninferior to standard care with systemic corticosteroids for acute exacerbation of chronic obstructive pulmonary disease (COPD) in a recent small study.

Researchers in Denmark performed a randomized controlled trial at three university-affiliated hospitals to investigate whether an algorithm based on eosinophil counts could reduce use of systemic corticosteroids without compromising safety in patients admitted for acute COPD exacerbation. Patients were eligible if they were at least 40 years of age, had known airflow limitation, had a subspecialist-verified diagnosis of COPD, and were prescribed systemic corticosteroids by the on-duty respiratory medicine physician. Eligible patients were randomly assigned to receive eosinophil-guided therapy or standard therapy with systemic corticosteroids. The study was not blinded.

On the first day of treatment, patients in both groups received 80 mg of IV methylprednisolone. Beginning on the second day, patients in the eosinophil-guided group received 37.5 mg of oral prednisolone daily for up to four days when they had a blood eosinophil count of 0.3 × 109 cells/L or higher. No prednisolone was given to this group on days when the eosinophil count did not meet this threshold. Patients who were discharged during the treatment period were prescribed a treatment based on the last measured eosinophil count for the remaining treatment days. Patients assigned to the control group received 37.5 mg of oral prednisolone daily from the second day of treatment for four days.

Number of days alive and out of the hospital within 14 days after study recruitment, assessed by intention to treat, was the study's primary outcome. Treatment failure at day 30, defined as recurrence of a COPD exacerbation requiring an ED visit, hospital admission, or treatment intensification; death by day 30; and duration of systemic corticosteroid treatment were secondary outcomes. The study results were published by The Lancet Respiratory Medicine on May 20 and appeared in the Aug. 1 issue.

Overall, between Aug. 3, 2016, and Sept. 30, 2018, there were 159 patients included in each group for the intention-to-treat analyses. Median age was 75 years in each group, and each group included more women than men (54% women in the eosinophil-guided group and 56% in the control group). No between-group difference was seen for the primary outcome (8.9 days alive and out of the hospital in the eosinophil-guided group versus 9.3 days in the control group; absolute difference, −0.4 day [P=0.34]). Forty-two patients in the eosinophil-guided group (26%) and 41 patients in the control group (26%) had treatment failure at 30 days (difference, 0.6%; P=0.90), and nine and six patients, respectively, had died (6% vs. 4%; difference, 1.9% [P=0.43]). Patients in the eosinophil-guided group had a lower median duration of systemic corticosteroid therapy than those in the control group (2 days vs. 5 days; P<0.0001).

The researchers concluded that potentially inappropriate corticosteroid use in patients hospitalized for acute COPD exacerbations can be decreased by using an eosinophil-guided algorithm in addition to clinical judgment. However, they cautioned that their trial was open-label and did not have enough power to detect potential differences in mortality rates between groups and noted that they did not measure eosinophil counts after discharge in the intervention group, among other limitations. They stressed that they were unable to completely rule out harm from the intervention and called for larger trials with sufficient power to detect worsening of such outcomes as readmission for acute COPD exacerbations and death.

New nonculture panel test accurately identified targeted bacteria in bloodstream infections

A new bacteria panel accurately diagnosed bloodstream infections caused by five common bacteria more quickly than cultures, a recent industry-funded study found.

The prospective study included 1,427 patients at 11 U.S. hospitals for whom blood cultures were ordered from Dec. 8, 2015, through Aug. 4, 2017. The performance of the T2Bacteria Panel, a direct-from-blood, nonculture test that identifies five types of bacteria (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli) was compared to a single set of blood cultures. The study was funded by the test's manufacturer, T2 Biosystems. Results were published by Annals of Internal Medicine on May 14 and appeared in the June 18 issue.

Results were positive for the targeted bacteria in 3% of blood cultures and 13% of the panel tests. The blood cultures took a mean of 38.5 hours (SD, 32.8) for positive results and 71.7 hours (SD, 39.3) for species identification. With the new test, the mean time to species identification was 3.61 (SD, 0.2) to 7.70 (SD, 1.38) hours, depending on the number of samples tested. For proven bloodstream infections, the test's sensitivity and specificity were both 90%. The negative predictive value was 99.7%. Ten percent of the samples had a negative blood culture but a positive test result; however, 60% of these were considered probable or possible bloodstream infections, based on a composite of clinical findings, blood culture results at other times, or culture results from nonblood sites. The authors noted that active antibiotic use was more common in these cases with discordant results, suggesting that the test might have particular value in patients already on antibiotics.

The study was limited by the low prevalence of positive blood cultures for the studied bacteria (only 39 out of 1,427 samples), the authors said. They also wrote that the test “should always be collected in conjunction with blood culture specimens because cultures identify bacteria not included in the panel and yield organisms for phenotypic antibiotic susceptibility testing” and “interpreted with careful consideration of patients' clinical status and antibiotic use.”

An accompanying editorial raised a number of other concerns about the test's clinical utility. “This study does not address whether the T2Bacteria Panel adds value to the management of patients with suspected BSI [bloodstream infection] or sepsis,” the editorialists said. Future research on the panel should assess whether its use shortens time to antibiotic therapy, time on therapy, or length of stay, as well as the impact on survival, laboratory workflows, and cost, the editorial said.

Age associated with risk for death in ICU survivors

For elderly patients discharged from an ICU, risk for long-term mortality standardized by age and sex was similar to that of the general population, but it was increased in younger ICU survivors, a recent study found.

Researchers in France used data from the French national health system database to perform a cohort study describing short-term and long-term mortality, defined as up to three years after discharge, by age in adult ICU patients. In-hospital mortality and mortality at three months and three years after discharge were determined for ICU admissions from Jan. 1 to Dec. 31, 2013. The study results were published May 10 by JAMA Network Open.

Image by Getty Images
Image by Getty Images

Overall, 133,966 patients were included in the study, 108,539 of whom were discharged from the hospital alive. Median age of the study cohort was 65 years, and 59.9% were men. Total in-hospital, three-month, and three-year mortality rates were 19.0%, 23.1%, and 39.7%, respectively. Of the patients who were discharged alive, 6.8% died by three months and 25.8% died by three years. Mortality risk increased progressively across all age strata after adjustment for several variables, with a sharp increase seen in those ages 80 years and older. Those in this age group had in-hospital and three-year postdischarge mortality rates of 30.5% and 44.9%, respectively, versus 16.5% and 22.5% in those younger than age 80 years. Total three-year mortality rate was 61.4% in patients who were ages 80 years and older and 35.1% in those younger than age 80 years.

The authors standardized the data by age and sex and found that younger patients had the highest excess mortality in the first year after hospital discharge and that this excess mortality was also present in the second and third year after discharge. This is likely related to the higher life expectancy of younger patients, the authors noted. In elderly patients, meanwhile, the mortality risk in these time frames was close to that of the general population. A strong association was seen between age and long-term mortality, with a 9-, 13- and 20-fold increase in three-year risk in patients ages 80 to 84 years, 85 to 89 years, and 90 years or older, respectively, versus patients younger than age 35 years.

The study was observational and included only French patients who were covered by national health insurance, the authors noted. Among additional limitations, they noted that data on risk behavior and body mass index were not available and that selection bias may have been present. They concluded that the overall three-year survival of patients discharged from ICUs in their study was approximately 60%; that mortality rates increased progressively with age, particularly in those 80 years of age and older; and that age- and sex-standardized mortality ratios were notably high in the study's younger patients immediately after ICU discharge. The last finding, they wrote, suggests that opportunities exist for improvement in this population and time frame.

The authors of an accompanying editorial said that this study, along with previous work, offers data to better inform clinicians' perspectives of critical illness outcomes in elderly patients and, in turn, conversations with patients and families. However, they noted that these data should “inform in broad strokes” and that clinicians should keep in mind that most elderly patients can and do survive a critical illness. “For elderly patients who receive critical care, the focus should be on ensuring that we continue to match care with preferences during the journey, update the goals, and focus on meeting their needs in the post-ICU and posthospital period, including discussions about whether they would want to go through the process again,” the editorialists wrote.

Thrombolysis may be effective up to 9 hours after stroke onset

Thrombolysis appears to be effective up to 9 hours after stroke onset in certain patients with acute ischemic stroke.

Researchers for the EXTEND (Extending the Time for Thrombolysis in Emergency Neurological Deficits) trial randomly assigned patients from study sites in Australia, New Zealand, Taiwan, and Finland to receive IV alteplase or placebo between 4.5 and 9 hours after stroke onset or after awakening with a stroke, as long as they were within 9 hours from the midpoint of sleep. Patients were eligible for the study if they were 18 years of age or older, had excellent functional status before enrollment, had a clinical severity score of 4 to 26 on the National Institutes of Health Stroke Scale (NIHSS), and had hypoperfused but salvageable brain regions on automated perfusion imaging. The study's primary outcome was a modified Rankin scale score of 0 or 1 at 90 days, where 0 indicates no symptoms and 6 indicates death. The risk ratio for this outcome was adjusted for age and NIHSS score at baseline. Results were published May 9 by the New England Journal of Medicine.

One hundred thirteen patients were randomly assigned to the alteplase group, and 112 patients were randomly assigned to the placebo group. The trial initially planned to enroll 310 patients but was terminated after 225 patients were enrolled because positive results from an earlier trial were published and clinical equipoise was lost. The primary outcome was seen in 40 patients in the alteplase group and 33 patients in the placebo group (35.4% vs. 29.5%; adjusted risk ratio, 1.44 [95% CI, 1.01 to 2.06]; P=0.04). No significant difference was seen in 90-day mortality between the two groups (13 patients vs. 10 patients [11.5% vs. 8.9%]; adjusted risk ratio, 1.17 [95% CI, 0.57 to 2.40]; P=0.67). Seven patients in the alteplase group and one patient in the placebo group had a symptomatic intracerebral hemorrhage (6.2% vs. 0.9%; adjusted risk ratio, 7.22 [95% CI, 0.97 to 53.54]; P=0.053). The researchers performed a secondary ordinal analysis of the distribution of modified Rankin scale scores and found no significant between-group difference in functional improvement at 90 days.

The researchers noted that their trial was terminated at 73% of the planned sample size and that they did not find a significant difference in functional improvement between groups. In addition, among other limitations, they pointed out that while the adjusted analyses found between-group differences in primary and secondary outcomes, the unadjusted analyses did not. They concluded, however, that alteplase therapy between 4.5 and 9 hours after stroke onset or awakening with stroke symptoms in patients who had a favorable perfusion profile was more likely to result in no or minor neurologic deficits versus placebo.

“Because of the limited power of our conclusions as a result of premature termination of the trial and the lack of a significant between-group difference in the secondary outcome of functional improvement, further trials of thrombolysis in this time window are required,” the authors wrote.