Antibiotics and AKI, stroke rehab, and more

Summaries from ACP Hospitalist Weekly.

Vancomycin plus piperacillin-tazobactam associated with higher AKI risk

Patients who received vancomycin plus piperacillin-tazobactam had significantly higher risk of acute kidney injury (AKI) than those on some other antibiotic regimens, a meta-analysis found.

The systematic review and meta-analysis included 15 published studies and 17 conference abstracts that assessed rates of AKI in hospitalized adult patients receiving antibiotics. At least 24,799 patients were included, and results were published online by Critical Care Medicine on Oct. 28, 2017, and appeared in the January 2018 issue.

Patients on vancomycin plus piperacillin-tazobactam had significantly higher rates of AKI than those on vancomycin monotherapy (odds ratio [OR], 3.40; 95% CI, 2.57 to 4.50), vancomycin plus cefepime or carbapenem (OR, 2.68; 95% CI, 1.83 to 3.91), or piperacillin-tazobactam monotherapy (OR, 2.70; 95% CI, 1.97 to 3.69). The overall rate of AKI was 16.7%, but it was 22.2% for vancomycin plus piperacillin-tazobactam and 12.9% for the comparator regimens. The meta-analysis authors calculated that the number needed to harm from a regimen of vancomycin plus piperacillin-tazobactam was 11. There was a trend toward shorter time to AKI with vancomycin plus piperacillin-tazobactam compared to the other regimens, but the difference was not significant.

The authors also conducted a subanalysis of the 968 critically ill patients in the included trials. In this subset, they found increased AKI risk with vancomycin plus piperacillin-tazobactam compared to vancomycin monotherapy (OR, 9.62; 95% CI, 4.48 to 20.68) but no significant difference compared to vancomycin plus cefepime or carbapenem (OR, 1.43; 95% CI, 0.83 to 2.47) or piperacillin-tazobactam monotherapy (OR, 1.35; 95% CI, 0.86 to 2.11).

This meta-analysis had similar results to previous meta-analyses on the topic, but it differed in that it did not include any pediatric patients and it was the first to calculate a number needed to harm with AKI, the authors believed. The possibility of significant differences between the regimens in critically ill patients should be investigated in future studies, they said.

“Given the number needed to harm of 11, along with the widespread use of this combination therapy, AKI with vancomycin plus piperacillin-tazobactam likely has a large impact on patient outcomes with the increased length of stay, costs, and mortality associated with AKI,” the authors wrote. Possible solutions include antibiotic stewardship interventions, such as using alternative antibiotics when appropriate, having institution-specific guidance on combination therapy, and creating antibiograms to determine susceptibility. The authors noted that the mechanism for the increased risk of AKI with vancomycin plus piperacillin-tazobactam is unknown and that the analysis was also limited by the risk of bias, including confounding by indication.

Mortality lower with prolonged vs. short-term IV infusion of antipseudomonal beta-lactams

Prolonged infusion of antipseudomonal beta-lactams for the treatment of patients with sepsis was associated with significantly less mortality than short-term infusion, a meta-analysis found.

The systematic review and meta-analysis included 22 randomized controlled trials (RCTs) with 1,876 patients that compared mortality or clinical efficacy of prolonged (continuous or ≥3 hours) versus short-term (≤60 minutes) infusion of antipseudomonal beta-lactams for sepsis. Carbapenems, penicillins, and cephalosporins were studied. Researchers considered age, Acute Physiology and Chronic Health Evaluation (APACHE) II score, severity of sepsis, and renal function. Results were published Oct. 25, 2017, by The Lancet Infectious Diseases and appeared in the January 2018 issue.

Prolonged infusion was associated with lower all-cause mortality than short-term infusion (risk ratio [RR], 0.70; 95% CI, 0.56 to 0.87). There was no heterogeneity (P=0.93, I2=0%), and a funnel plot and the Egger's test (P=0.44) showed no evidence of publication bias. Almost all subgroup and sensitivity analyses showed that prolonged infusion was associated with at least a trend toward lower all-cause mortality than short-term infusion.

“Although the majority of RCTs included only ICU patients, prolonged infusion might benefit all hospitalised patients with sepsis; further studies in specific subgroups of patients according to age, sepsis severity, degree of renal dysfunction and immunocompetence are warranted,” the authors concluded. “The contribution of therapeutic drug monitoring on the outcome of patients treated with prolonged infusion of antipseudomonal β-lactams merits further study.”

The review showed a clear mortality benefit for ICU patients from prolonged infusion, an accompanying comment observed. The commenters added that prolonged infusion is easy to apply in the ICU, and no harms have been shown.

“With current evidence it seems that we should standardise prolonged dosing of β-lactams in ICUs,” the editorial stated. “A loading dose equal to the short-term dose was used in most studies included in the systematic review. When using continuous infusion the dosing regimen should start with a loading dose equal to the short-term dose and continue with the total recommended daily dose administered by prolonged infusion. In case of extended infusion (2-3 h) the recommended doses should be used.”

Model may help predict patient outcome after stroke rehab

A recently developed model may help predict whether rehabilitation will significantly improve stroke patients' physical function and independence.

Photo by Thinkstock
Photo by Thinkstock.

Researchers in Italy derived two models from 717 patients, one for the study's primary outcome and one for the secondary outcome. All patients had been admitted to the hospital for rehab after stroke. The primary outcome was achievement of a motor Functional Independence Measure score of more than 61 points at discharge, indicating mild stroke impairment. The secondary outcome was recovery to a physical independence grade of 5 or above in the Functional Independence System, which indicates that a patient needs no more than supervision to groom, dress the upper body, or transfer from a chair to a bed or transfer onto a toilet; needs no more than minimal assistance to bathe, dress the lower body, or use a wheelchair or walk; functions at least at modified independence in eating and in bowel and bladder movements; and may need total assistance to climb stairs.

Model 1 included age, time from stroke to rehab admission, motor and cognitive Functional Independence Measure scores at admission, and unilateral neglect. Model 2 included age, male sex, time since stroke onset, and motor and cognitive Functional Independence Measure scores at admission. Each model was prospectively validated after derivation in 875 patients. The study results were published online by Stroke on Oct. 19, 2017.

Mean patient age was 72 years in the validation cohort and 70 years in the derivation cohort. Patients in the validation cohort were more likely to have been admitted earlier to inpatient rehab units (mean time from stroke to admission, 15 days vs. 25 days). Overall, 28.7% of patients achieved the primary outcome in the derivation cohort and 31.3% achieved it in the validation cohort, while the secondary outcome was achieved by 13.9% and 18.3%, respectively. Excellent discrimination was seen in both models. The area under the curve was 0.883 and 0.913 for model 1 and model 2, respectively, in the derivation cohort. In the validation cohort, the area under the curve for each model was 0.866 and 0.850, respectively. An independent association was seen between better four-year survival and both improved physical functioning (hazard ratio, 0.43; 95% CI, 0.25 to 0.71; P=0.001) and level of independence needing only supervision (hazard ratio, 0.32; 95% CI, 0.14 to 0.68; P=0.004).

The authors noted that their study was retrospective, that unmeasured or undocumented factors may have affected the outcome, and that median time from stroke to rehab admission was longer than in the U.S. for comparable populations, among other limitations. However, they concluded that the model they developed provides “an easy-to-use, accurate, and validated predictive tool for potential application in rehabilitation research and stroke management.”

Procalcitonin testing reduced antibiotic use and mortality in acute respiratory infections

Using procalcitonin levels to guide antibiotic treatment reduced antibiotic side effects and mortality in patients with acute respiratory infections, according to a recent meta-analysis.

The analysis included 26 trials in which patients with respiratory infections were randomly assigned to either receive antibiotics based on procalcitonin concentrations or be treated as controls. More than 6,000 patients from 12 countries were included. Two of the trials were conducted in primary care settings, while 11 were in patients with lower respiratory tract infection in an ED or medical ward, and 13 were in ICU patients with sepsis due to lower respiratory tract infections. Results were published by The Lancet Infectious Diseases on Oct. 13, 2017, and appeared in the January 2018 issue.

Thirty-day mortality was significantly lower in the procalcitonin-guided patients than in controls (9% vs. 10%; adjusted odds ratio [OR], 0.83; 95% CI, 0.70 to 0.99; P=0.037). The mortality benefit was similar across subgroups by setting and type of infection, although researchers noted that mortality rates were very low in primary care and acute bronchitis, so the effect of procalcitonin on these patients could not be assessed.

Use of procalcitonin was also associated with reductions in antibiotic exposure (5.7 days vs. 8.1 days; 95% CI for reduction in days, −2.71 to −2.15; P<0.0001) and antibiotic side effects (16% vs. 22%; adjusted OR, 0.68; 95% CI, 0.57 to 0.82; P<0.0001). There were no significant differences in length of ICU or hospital stay based on procalcitonin test use.

This is the first systematic review and meta-analysis “to describe significant and relevant improvements in clinical outcomes and specifically a decreased risk for mortality for patients with acute respiratory infections, when procalcitonin was used to guide antibiotic treatment decisions,” the authors said. Procalcitonin testing may reduce mortality by enabling clinicians to identify nonresponders and look for alternative explanations for symptoms, among other possible explanations, the authors speculated.

The study's results suggest that widespread implementation of procalcitonin protocols might not only improve antibiotic management and outcomes for patients with acute respiratory infections but also help to combat the threat of antibiotic resistance, the authors said.

An accompanying comment praised the study but cautioned that procalcitonin will not solve the antibiotic overuse problem, noting that “the clinical reasoning behind antibiotic-related decisions is also strongly influenced by patient and disease characteristics, such as severity, and physicians' previous experiences, which can easily override any algorithm recommendation.” However, the commenters added that “if procalcitonin can safely decrease unnecessary antibiotic use in different settings, even if imperfectly, it is already worthwhile.”

Predictors of intubation vary by oxygen delivery method in patients with acute hypoxemic respiratory failure

Predictors of intubation in patients with acute hypoxemic respiratory failure seem to vary according to the type of noninvasive oxygenation therapy received, according to a study.

Researchers performed a post hoc analysis of randomized clinical trials involving 23 ICUs to identify factors associated with intubation in patients with acute hypoxemic respiratory failure. Included patients had a respiratory rate above 25 breaths per minute and a PaO2/FiO2 ratio of 300 mm Hg or lower and were treated with standard oxygen, high-flow nasal cannula oxygen, or noninvasive ventilation. The study's main outcome was to identify early factors—at baseline and at one hour—associated with intubation. Factors associated with 90-day mortality rates were also examined. The study results were published online Nov. 2, 2017, by Critical Care Medicine and appeared in the February 2018 issue.

A total of 310 patients were included in the study, 72 (23%) with mild hypoxemia, 165 (53%) with moderate hypoxemia, and 73 (24%) with severe hypoxemia. Ninety-four patients were treated with standard oxygen, 106 were treated with high-flow nasal cannula oxygen, and 110 were treated with noninvasive ventilation. Overall, 45% of the study population (139 of 310 patients) required intubation, with signs of persisting or worsening respiratory failure being the most common reason. Bilateral pulmonary infiltrates were more likely in patients who needed intubation, and this group was also more likely to have a higher respiratory rate and a lower PaO2 at baseline compared with those who did not need intubation.

One hour after treatment began, intubation was more likely in patients receiving standard oxygen who had a respiratory rate of 30 breaths per minute or greater (odds ratio, 2.76; P=0.03). For patients receiving high-flow nasal cannula oxygen, increased heart rate one hour after the start of treatment was the only intubation predictor (odds ratio, 1.03; P<0.01), while for patients receiving noninvasive ventilation, independent predictors were a PaO2/FiO2 ratio less than or equal to 200 mm Hg (adjusted odds ratio, 4.26; P=0.003) and a tidal volume above 9 mL/kg of predicted body weight (adjusted odds ratio, 3.14; P=0.02). A tidal volume above 9 mL/kg of predicted body weight was also independently associated with mortality in the noninvasive ventilation group (adjusted odds ratio, 4.51; P=0.004).

The authors noted that their study had a post hoc design and that their results may apply only to patients with severe hypoxemic community-acquired pneumonia and no nonrespiratory organ dysfunction, among other limitations. However, they concluded that one hour after treatment initiation, a high respiratory rate in patients receiving standard oxygen and a high tidal volume in patients receiving noninvasive ventilation are associated with likelihood of intubation. They also noted an independent association between high tidal volume one hour after the start of treatment and 90-day mortality in patients receiving noninvasive ventilation. “When the tidal volume is so elevated, clinicians should be cautious concerning [noninvasive ventilation] prolongation, which could entail an increased risk of volutrauma,” the authors wrote.

Fondaparinux associated with fewer HIT complications in industry-funded study

Treatment of suspected heparin-induced thrombocytopenia (HIT) with fondaparinux led to better outcomes than treatment with the anticoagulants approved for this indication, an industry-funded study found.

The multicenter registry study included 195 hospitalized patients in Germany who had been diagnosed with HIT and had at least an intermediate clinical risk of HIT (4Ts score ≥4 points). Eighty-four of them (43.1%) received first-line treatment with fondaparinux, while 61 patients (31.3%) received danaparoid, 46 (23.6%) received argatroban, and 4 (2.1%) received lepirudin. The main outcomes were HIT-specific complications (thromboembolic venous/arterial events, amputations, recurrent/persistent thrombocytopenia, skin lesions) and bleeding. The study was funded by GlaxoSmithKline. Results were published in the Nov. 28, 2017, Journal of the American College of Cardiology.

HIT-specific complications occurred in none of the fondaparinux-treated patients and 11.7% of the patients treated with the other anticoagulants. All-cause in-hospital mortality rates were 0% during fondaparinux treatment and 14.4% with the other anticoagulants. Bleeding complications occurred in 4.8% of fondaparinux patients and 6.3% of patients on the other drugs. The authors also tried to determine which of the patients with suspected cases actually had “true” HIT. Based on clinical and laboratory features, they found that at least 35 of the patients treated with fondaparinux had “true” HIT, leading them to conclude that fondaparinux is effective and safe in suspected acute HIT.

“Further data from randomized controlled trials are urgently needed because lepirudin was recalled from the market; danaparoid access has been limited and is not approved in the United States; and argatroban is contraindicated in patients with impaired liver function, and activated partial thromboplastin time confounding may interfere with monitoring,” the authors wrote. They also called for discussion of changing guidelines on fondaparinux use in suspected HIT from “off-label use only” to “possible use in patients with intermediate (or even high) risk of HIT.”

An accompanying editorial comment agreed that the results of this and other studies indicate that fondaparinux is an appropriate anticoagulant for patients with HIT. The editorial offered a few tips on use, including caution (and adjusted dosing) in patients with renal insufficiency and awareness of the possibility of “cross-reactive” HIT antibodies for fondaparinux. The editorial noted that direct oral anticoagulants have also recently been used in patients with probable HIT and that these drugs, along with fondaparinux, appear to be replacing the approved anticoagulants for HIT in practice.

Noninvasive cardiac testing in the ED leads to increased lengths of stay with no clinical improvement

Noninvasive testing to rule out acute coronary syndrome (ACS) in low- and intermediate-risk patients who present to the ED with chest pain seems to provide no clinical benefit over clinical evaluation alone, while increasing health care resource use, according to a retrospective analysis.

To compare the effects of adding noninvasive testing methods such as coronary computed tomographic angiography (CCTA) or stress testing to clinical evaluation alone, researchers conducted a retrospective analysis of the randomized multicenter Rule Out Myocardial Ischemia/Infarction by Computer Assisted Tomography (ROMICAT-II) trial. The trial included 1,000 patients who presented to any of 9 U.S. EDs with chest pain but had negative biomarkers and a nonischemic electrocardiogram result.

The primary outcome was length of stay, while secondary outcomes included hospital admission, direct ED discharge, downstream testing, rates of invasive coronary angiography, revascularization, major adverse cardiac events (MACE), repeated ED visit or hospitalization for recurrent chest pain at 28 days, and cost. Safety end points were missed ACS and cumulative radiation exposure during the index visit and follow-up period. Results were published online Nov. 14 and in the February 2018 JAMA Internal Medicine.

Of 1,000 patients, 118 patients (12%) received only clinical evaluation, while 882 (88%) received CCTA or stress testing. Patients who underwent clinical evaluation alone had shorter length of stay (20.3 vs. 27.9 hours; P<0.001), lower rates of diagnostic testing (P<0.001) and angiography (2% vs. 11%; P<0.001), lower median costs ($2,261.50 vs. $2,584.30; P=0.009), and less cumulative radiation exposure (0 vs. 9.9 mSv; P<0.001) during the 28-day study period.

The patients who received clinical evaluation alone had lower rates of diagnosis of ACS (0% vs. 9%; P<0.001), coronary angiography (0% vs. 10%; P<0.001), and percutaneous coronary intervention (0% vs. 4%; P=0.02) during the index visit. In the 28-day follow-up period, there was no difference in rates of percutaneous coronary intervention (2% vs. 5%; P=0.15), coronary artery bypass surgery (0% vs. 1%; P=0.61), return ED visits (5.8% vs. 2.8%; P=0.08), or MACE (2% vs. 1%; P=0.24).

The authors concluded that for such patients, adding noninvasive cardiac testing to clinical evaluation leads to longer stay, more downstream testing, more radiation exposure, and greater cost without evidence of improving clinical outcomes, in addition to other potential negative consequences. “The routine use of CCTA, as has been advocated by some, in the 10 million patients who present to the ED with chest pain would be expected to result in thousands of new cases of cancer,” the authors wrote.

An editor's note said the results are not definitive because of study power and a lack of randomization and should prompt a randomized controlled trial. “While awaiting a trial, clinicians may wish to consider following patients with low-risk chest pain and reserving noninvasive testing if indicated by subsequent events.”

Hospitals with more postdischarge ED visits have fewer readmissions, study finds

In the 30 days after a hospitalization for acute myocardial infarction (AMI), heart failure, or pneumonia, almost one in 10 patients is treated and released from an ED, according to a recent study.

The cross-sectional analysis of Medicare fee-for-service data between July 2011 and June 2012 included 157,035 patients hospitalized for AMI, 391,209 patients hospitalized for heart failure, and 342,376 patients hospitalized for pneumonia. Treat-and-discharge ED visits occurred within 30 days in 9% of the AMI patients and 8% of the heart failure and pneumonia patients.

Photo by Thinkstock
Photo by Thinkstock.

The study found wide variation among the hospitals in their ED visit rates. For AMI, the 5th percentile rate was 2.8%, while the 95th percentile was 14.3%; the respective rates were 3.0% and 13.3% for heart failure and 2.4% and 13.2% for pneumonia. There was also a statistically significant inverse correlation between postdischarge ED visit rates and readmission rates: AMI, −0.23; heart failure, −0.29; and pneumonia, −0.18. The study was published online by the Journal of Hospital Medicine on March 15.

The results suggest that “that publicly reported readmission measures are capturing only a portion of postdischarge acute-care use,” the authors said. They noted that the study also found that the majority of ED visits after discharge were for conditions unrelated to the index hospitalization and that certain hospital characteristics were associated with postdischarge ED visits. Rural and safety-net hospitals had higher rates, which may suggest that some of the ED visits were driven by lack of access to primary care.

The authors offered a number of hypotheses to explain the inverse association between readmissions and ED visits, including that EDs may be serving as gatekeepers, that hospitals with greater ED access see patients sooner when their condition is less severe, or that hospitals that admit fewer patients would have more ED treat-and-discharge visits because fewer ED visits end in admissions. They called for further research into the role of the ED in supporting care transitions for recently hospitalized patients.

An accompanying editorial said that the results, particularly the correlation between postdischarge ED visits and readmissions, should be interpreted cautiously, but they might hold lessons for improving care. “If hospitals with high postdischarge ED visit rates can deliver high-quality care while truly arresting or reversing readmission-bound trajectories, then the strategies employed by these hospitals should inspire emulation, innovation, and dissemination,” the editorial said.

Hospitals' heart failure mortality rates associated with patients' long-term outcomes

Thirty-day mortality rates may be an effective measure of hospitals' quality of care for heart failure (HF) patients, according to a recent study.

The longitudinal observational study used data from the Get With the Guidelines-HF registry to examine treatment and outcomes in 106,304 patients admitted with HF to 317 hospitals from Jan. 1, 2005, to Dec. 31, 2013. The patients' median age was 81 years, 54.1% were women, and 79.6% were white. Results were published online by JAMA Cardiology on March 12.

The hospitals were divided into quartiles based on their 30-day risk-standardized mortality rates (RSMR), which ranged from 8.6% in the best quartile to 10.7% in the worst. The study found that the hospitals in the best quartile had greater availability of advanced HF therapies, cardiac surgery, and percutaneous coronary intervention. There was an association between hospitals' 30-day RSMR and long-term mortality risk in patients who survived the first 30 days. In adjusted analyses, patients admitted to hospitals in the worst quartile had 14% higher relative hazards of five-year mortality (95% CI, 10% to 18%) compared to those treated at the hospitals with the best 30-day RSMR.

The study authors concluded that differences among hospitals in mortality of HF patients “persisted long term, suggesting that 30-day RSMR may be a useful HF performance metric to incentivize quality care and improve long-term outcomes.” In comparison, 30-day readmission rates, which make up a larger percentage of CMS’ financial quality incentive system, have “limited utility” as a measure of quality, the authors said.

Other significant findings of the study include the variation found among hospitals in their adherence to recommended processes of care, including use of implantable cardioverter defibrillators, cardiac resynchronization therapies, and advanced HF therapies, as well as postdischarge follow-up. The study also found that the association between hospitals' 30-day RSMR and long-term mortality was stronger for patients with reduced ejection fraction, which might be explained by there being more available therapies to extend their lives than are available for patients with preserved ejection fraction.

The study was limited by its observational design and therefore could not establish causation between 30-day RSMR and long-term survival, the authors noted.