Stewardship, stroke mimics

Summaries from ACP Hospitalist Weekly.

Pharmacist-led antimicrobial stewardship strategies worked in community hospitals

Antimicrobial stewardship can be successfully implemented in community hospitals, a recent study found.

Image by Getty Images
Image by Getty Images

From October 2014 through October 2015, researchers implemented two core antimicrobial stewardship interventions at four community hospitals with limited infectious diseases physician support in North Carolina (median bed size, 305; range, 102 to 425). Both interventions trained one or more pharmacists at each site to be antibiotic stewards and specifically targeted vancomycin, piperacillin-tazobactam, and the antipseudomonal carbapenems on formulary. Results were published on Aug. 16, 2019, by JAMA Network Open.

The first stewardship strategy, modified preauthorization, required the prescriber to receive pharmacist approval for continued use of the antibiotic after the first dose. (The study was initially designed to test strict preauthorization, in which the pharmacist had to give approval before the first dose, but participating hospitals deemed that infeasible.) In the second strategy, postprescription audit and review, a pharmacist contacted the prescriber about antibiotic appropriateness after 72 hours of therapy. Two hospitals performed modified preauthorization for six months, then postprescription audit and review for six months after a one-month washout, while the other two hospitals did the reverse.

Overall, 2,692 patients (median age, 65 years; 52.5% women; 38.9% African-American) were included. The interventions took a median of 95 days to be approved by the hospitals (range, 56 to 119 days). The pharmacists performed a median of 350 modified preauthorization interventions and 298 postprescription audit and review interventions per hospital. The median time dedicated to the interventions varied by site, ranging from a median of five to 19 hours per week.

Antimicrobials were deemed inappropriate two times as often during the postprescription audit and review period versus the modified preauthorization period (41.0% vs. 20.4%; P<0.001). Pharmacists recommended dose changes more often during the modified preauthorization intervention (15.9% vs. 9.6%; P<0.001) and de-escalation more often during postprescription audit and review (29.1% vs. 13.0%; P<0.001). Overall antibiotic use decreased during postprescription audit and review compared with historical controls (mean days of therapy per 1,000 patient-days, 925.2 vs. 965.3; mean difference, −40.1 [95% CI, −71.7 to −8.6]) but not during modified preauthorization (mean days of therapy per 1,000 patient-days, 931.0 vs. 926.6; mean difference, 4.4 [95% CI, −55.8 to 64.7]). The study authors concluded that strict prior authorization was not feasible in the participating hospitals, but that postprescription audit and review “was a feasible and effective strategy for antimicrobial stewardship in settings with limited resources and expertise.”

Very few multicenter studies have assessed stewardship program implementation in community hospitals, and the findings from this study are likely to be generalizable, an accompanying commentary noted. Participating hospitals lacked infectious diseases resources to support the stewardship program and training in antibiotic stewardship, although they were relatively large and were part of the Duke Antimicrobial Stewardship Outreach Network, the commentary noted.

Overall, the results show that preauthorization and postprescription audit and review can be modified based on community hospitals' local resources and personnel, the editorialists concluded. “Arthur Ashe once said, ‘Start where you are. Use what you have. Do what you can.’ Ashe was not referring to [antimicrobial stewardship programs], but he might as well have been,” they wrote.

Complications rare when stroke mimics are treated with tPA, study finds

Relatively few patients who received IV tissue-type plasminogen activator (tPA) were found to have stroke mimics, and their rates of complication from treatment were low, according to a recent study.

The retrospective study included 72,582 patients treated with tPA for suspected ischemic stroke at 485 U.S. hospitals participating in the Get With The Guidelines–Stroke Registry between January 2010 and December 2017. The researchers focused on patients with stroke mimics, defined as those who presented with stroke-like symptoms, but after workup were determined not to have had a stroke or transient ischemic attack. Results were published by Circulation: Cardiovascular Quality and Outcomes on Aug. 15, 2019.

Overall, 3.5% of the studied tPA treatments were given to patients found to have stroke mimics. Among these patients, 38.2% had final nonstroke diagnoses of migraine, functional disorder, seizure, and electrolyte or metabolic imbalance. Compared to patients with true ischemic strokes, those with mimics were younger (median age, 54 vs. 71 years), had less severe National Institute of Health Stroke Scale scores (median, 6 vs. 8), and had lower prevalence of cardiovascular risk factors, except for prior stroke/transient ischemic attack (31.3% vs. 26.1%). The rate of symptomatic intracranial hemorrhage (sICH) was lower in stroke mimic patients (0.4% vs. 3.5%; adjusted odds ratio [OR], 0.29; 95% CI, 0.17 to 0.50), as was in-hospital mortality (0.8% vs. 6.2%; adjusted OR, 0.31; 95% CI, 0.20 to 0.49).

This study is the largest multicenter investigation of stroke mimics, according to its authors, and the observed rate of stroke mimics is in the low range of those previously reported. “The strong emphasis now placed on reducing door-to-needle times may lead to increased treatment of stroke mimics. Nonetheless, the low number of sICH in stroke mimics found in this study (0.4%) compared with true ischemic stroke (3.5%) as well as the lower overall complications from tPA (1.5% versus 6.9%) demonstrate the minimal risk of treating patients with stroke mimic,” the authors said, adding that “a small increase in the treatment of stroke mimics may represent a reasonable tradeoff for earlier treatment time of patients with acute stroke and their subsequent improved outcomes.”

Limitations of the study include possible reporting bias, as it relied on voluntary reporting of treatment of stroke mimics, and the entire registry is a voluntary program. In addition, “this study does not address the important outstanding question on the clinical outcomes of stroke mimic cases treated with tPA compared with other stroke mimics not treated with tPA,” the authors said.

An accompanying editorial noted that “clinicians, patients, and families often spend an inordinate amount of time considering this treatment decision.” MRI can be helpful in cases of diagnostic uncertainty, but there is variation among hospitals in the speed with which MRI can be completed, the editorialists noted. Future research should look at new diagnostic techniques for stroke, but in the interim, this study can give physicians greater confidence about promptly offering tPA, the editorial concluded.

Interrupting DOACs for surgery associated with few major bleeds, clots in afib patients

A perioperative strategy of direct oral anticoagulant (DOAC) interruption that did not require the use of heparin bridging or coagulation function testing was associated with low rates of major bleeding and arterial thromboembolism in patients with atrial fibrillation, a study found.

Researchers assessed the safety of a standardized perioperative DOAC management strategy in 3,007 adults (mean age, 72.5 years; 66.1% men) with atrial fibrillation in the Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) cohort study. Participants were long-term users of apixaban (n=1,257 [41.8%]), dabigatran (n=668 [22.2%]), or rivaroxaban (n=1,082 [36.0%]) and were scheduled for an elective surgery or procedure. They were enrolled from Aug. 1, 2014, through July 31, 2018, at 23 centers in the U.S., Canada, and Europe.

The DOAC interruption and resumption strategy was based on pharmacokinetic properties, procedure-associated bleeding risk, and creatinine clearance levels. DOAC regimens were omitted for one day before procedures with low bleeding risk and for two days before procedures with high bleeding risk. Regimens were resumed one day after low-bleeding-risk procedures and two to three days after high-bleeding-risk procedures. Patients were followed for 30 days after operation. The main outcomes were major bleeding and arterial thromboembolism (ischemic stroke, systemic embolism, and transient ischemic attack). Results were published online on Aug. 5, 2019, by JAMA Internal Medicine.

The researchers' hypothesis that the PAUSE management strategy would exclude a 2% rate of major bleeding was supported in the dabigatran group, but not in the apixaban or rivaroxaban groups, while their hypothesis that the strategy would exclude a 1.5% rate of arterial thromboembolism was supported in all three cohorts. At 30 days, the postoperative rate of major bleeding was 1.35% (95% CI, 0% to 2.00%) in the apixaban group, 0.90% (95% CI, 0% to 1.73%) in the dabigatran group, and 1.85% (95% CI, 0% to 2.65%) in the rivaroxaban group. The rate of arterial thromboembolism was 0.16% (95% CI, 0% to 0.48%) in the apixaban group, 0.60% (95% CI, 0% to 1.33%) in the dabigatran group, and 0.37% (95% CI, 0% to 0.82%) in the rivaroxaban group. A per protocol analysis found that a 2% rate of major bleeding was excluded in the dabigatran and apixaban groups, but not in the rivaroxaban group, and a 1.5% rate of arterial thromboembolism was excluded in all three cohorts.

Limitations of the study include its cohort study design and the fact that the dabigatran group did not reach the expected sample size, the authors noted. They added that most participants were white and that the results are not generalizable to edoxaban, which was not available when the study began. They concluded that the strategy is “likely to be easily adoptable in clinical practice.”

PE rarely found in patients presenting to ED with syncope

Pulmonary embolism (PE) was rare among patients who presented to an ED with syncope, even after two years of follow-up, a recent international study found.

The Basel Syncope Evaluation Study is an ongoing prospective international study that reported data on 1,397 unselected patients from 13 hospitals in eight countries who presented to an ED with syncope from May 2010 to February 2017 and were stable enough to provide informed consent. Inclusion criteria included age at least 40 years and presentation within 12 hours of the syncopal event. The patients' median age was 69 years, and 42% were women. Pre-test clinical probability for PE was assessed using the two-level Wells score and D-dimer testing with age-adapted cutoffs. Results were published by JACC on Aug. 5, 2019.

PE was detected at presentation in 19 patients (1.4%; 95% CI, 0.87% to 2.11%). Two-year follow-up data were available for 1,156 of the patients (83%), and the incidence of new PE or cardiovascular death during that period was 0.9% (95% CI, 0.5% to 1.5%). Of the original 1,397 patients, 47% were hospitalized for syncope and PE was detected at presentation in 15 of them (2.3%; 95% CI, 1.4% to 3.7%).

The study authors noted that “the prevalence of PE observed in this study was substantially lower than recently suggested in an Italian pilot study of 560 patients hospitalized for a first syncope (17.3%) that largely relied on imaging data with the inherent and well-documented risk of overestimation due to false-positive results.” Other recent studies trying to confirm the Italian findings have also found PE to be uncommon among syncope patients, which suggests that PE workups should be based on factors such as dyspnea, signs of deep venous thrombosis, or electrocardiogram findings, the authors said.

The study also “put the pros and cons of functional versus anatomic testing into perspective,” said the authors, who advocated use of the combined functional and anatomic diagnostic workup applied in their study. Limitations of the study include that the results can't be extrapolated to patients presenting to primary care or more than 12 hours after symptom onset.

An accompanying editorial reviewed the differences between the current study and the previous Italian pilot. Patients in the Italian study were older, were all hospitalized, and were all being treated for their first episode of syncope. Clinicians should apply the best attributes of both studies to clinical practice, the editorialist recommended. “For patients with first-time syncope, minimal workup for PE with a clinical probability assessment and D-dimer makes sense. If this workup points to a high probability for PE, imaging should be obtained,” the editorial said. “Perhaps the relation between syncope and PE is best described as the ‘progeny of a horse and a zebra.’”

Prone positioning, venovenous extracorporeal membrane oxygenation may help improve outcomes in moderate to severe ARDS

Prone positioning and venovenous extracorporeal membrane oxygenation are associated with better outcomes when added to lung protective ventilation in patients with acute respiratory distress syndrome (ARDS), a recent systematic review and network meta-analysis found.

Researchers analyzed randomized clinical trials that used lung protective ventilation and other interventions in adults with moderate to severe ARDS in the ICU. The goal was to compare and rank therapeutic strategies and determine which were associated with reduced mortality. The therapeutic strategies considered were lung protective ventilation, open-lung strategies such as lung recruitment maneuvers or positive end-expiratory pressure, neuromuscular blockade, inhaled nitric oxide, high-frequency oscillatory ventilation, prone positioning, and venovenous extracorporeal membrane oxygenation. The primary outcome was 28-day mortality, with barotrauma as a secondary outcome. The results were published July 31, 2019, by JAMA Network Open.

Twenty-five trials involving 7,743 patients were included in the network meta-analysis. Of these patients, 2,686 (34.6%) died within 28 days. Prone positioning (risk ratio, 0.69 [95% credible interval, 0.48 to 0.99]; low-quality evidence) and venovenous extracorporeal membrane oxygenation (risk ratio, 0.60 [95% credible interval, 0.38 to 0.93]; moderate-quality evidence) were associated with significantly lower 28-day mortality versus lung protective ventilation alone. In the 18 trials that reported barotrauma, it occurred in 448 of 6,258 patients (7.2%), with no superiority seen for any of the studied interventions.

The researchers noted that their study could have been subject to bias, that only short-term mortality was examined, and that they did not account for covariates such as age in the final models of the network meta-analysis, among other limitations. They concluded that their results support the use of prone positioning and venovenous extracorporeal membrane oxygenation in addition to lung protective ventilation in certain patients with ARDS. Prone positioning should be recommended as an adjunctive therapy in adults with moderate to severe disease, while venovenous extracorporeal membrane oxygenation should be recommended in severe disease only, since both of the included trials examining the latter intervention involved only patients with severe ARDS, they wrote. Venovenous extracorporeal membrane oxygenation could also be considered as an early treatment strategy in severe ARDS, the authors said, based on their findings and on other recent data.

Hospitals' volume of PE treatment associated with 30-day PE-related mortality

Hospitals that treated more pulmonary embolisms (PEs) had lower rates of patient mortality from the condition, a recent study found.

The population-based cohort study used data from the Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) registry on 39,257 consecutive patients treated for a confirmed diagnosis of acute symptomatic PE at any of 353 hospitals in 16 countries in 2001 to 2018. The study's main outcome was PE-related mortality within 30 days after diagnosis. Results were published by The BMJ on July 29, 2019.

Patients treated at a hospital in the highest quarter of PE volume (>40 PEs per year) had a 44% reduction in the adjusted odds of PE-related 30-day mortality compared with those at hospitals in the lowest quarter (<15 PEs per year; adjusted risk, 1.3% vs. 2.3%; adjusted odds ratio [OR], 0.56 [95% CI, 0.33 to 0.95]; P=0.03). All-cause mortality was not significantly different between these groups (adjusted OR, 0.78; 95% CI, 0.50 to 1.22; P=0.28), nor were rates of recurrent venous thromboembolism (OR, 0.76; 95% CI, 0.49 to 1.19) or major bleeding (OR, 1.07; 95% CI, 0.77 to 1.47) among patients who survived PE.

“We observed a consistent dose-response relation between hospital volume and pulmonary embolism related mortality,” the study authors said. They noted that the results were consistent with adjustment, across major subgroups of patients, and with different modeling assumptions and that patients at the higher-volume hospitals had greater comorbidity burden and signs of clinical severity.

The study's design did not allow for determination of causality, but the authors did offer their theories on why lower-volume hospitals might have higher PE mortality. Care teams could be less experienced at these facilities, and, in fact, the study did find lower adherence to evidence-based guidelines for PE treatment at the lower-volume hospitals. The authors suggested that clinician education might be a solution to this and should be tried in future studies.

“Thus, initiatives that could help improve the practitioners' knowledge and adherence to guidelines recommendations at low volume hospitals, timely transfer of patients with pulmonary embolism (especially severe cases) to high volume hospitals, and dissemination of [pulmonary embolism response teams] across the hospitals (such as multidisciplinary teams caring for patients with ST elevation myocardial infarction) could be considered,” they wrote.

Flexible visitation, ICU diaries have little effect on delirium, PTSD

Flexible family visitation and ICU diaries did not appear to improve outcomes in critically ill patients, according to two recent studies.

In the first study, researchers performed a cluster-crossover randomized trial of flexible visitation (up to 12 hours a day) in 36 ICUs in Brazil that normally used restricted visiting hours (<4.5 hours per day). Nineteen ICUs began the trial with flexible visitation, and 17 began with restricted visitation. The primary outcome was incidence of delirium during the ICU stay, as assessed by using the Confusion Assessment Method (CAM)-ICU. ICU-acquired infections, anxiety and depression in family members, and burnout in ICU staff were secondary outcomes. Results were published July 16, 2019, by JAMA.

Overall, 1,685 patients, 1,295 family members, and 826 clinicians enrolled in the trial, and of these, all of the patients, 1,060 family members (81.8%), and 737 clinicians (89.2%) completed it. A significantly higher mean daily duration of visits was seen with flexible visitation (4.8 hours vs. 1.4 hours; adjusted difference, 3.4 hours [95% CI, 2.8 to 3.9 hours]; P<0.001). However, delirium incidence during the ICU stay did not differ significantly between flexible and restricted visitation (18.9% vs. 20.1%; adjusted difference, −1.7% [95% CI, −6.1% to 2.7%]; P=0.44). ICU-acquired infections and staff burnout did not differ significantly by visitation schedule, although family members had significantly better median anxiety and depression scores with flexible visitation.

The researchers noted that their study was done in only one country, that recruitment bias might have affected their results, and that the effects of flexible visitation on long-term outcomes were not evaluated, among other limitations. In addition, they said that the relatively short duration of the flexible visitation intervention might have affected its ability to benefit patients and that many patients at higher risk for delirium, such as those in prolonged coma, were excluded. They concluded, however, that a flexible family visitation policy in ICUs did not significantly reduce delirium incidence compared with standard restricted visiting hours.

Image by Getty Images
Image by Getty Images

In the second study, also published July 16, 2019, by JAMA, researchers examined the effect of an ICU diary on psychological consequences for patients, specifically symptoms of post-traumatic stress disorder (PTSD). The multicenter, randomized clinical trial was done at 35 ICUs in France and involved 709 adult patients, with one family member each, who received mechanical ventilation within 48 hours after ICU admission for at least two days. Of these, 355 patients were assigned to the intervention group and had an ICU diary completed by clinicians and family members, while 354 were assigned to the control group and received usual care. Patients were told about the diary a few days before discharge and received it at or close to discharge.

The main outcome measure was significant symptoms of PTSD as measured three months after ICU discharge and defined as a score greater than 22 on the Impact Event Scale-Revised (IES-R). Secondary outcomes assessed at three months were significant PTSD symptoms in family members, significant anxiety and depression symptoms in patients and family members, and patient memories of the ICU stay.

A total of 339 of 657 patients (51.6%) completed the trial. Significant PTSD symptoms were reported at three months in 49 of 164 patients (29.9%) in the intervention group and 60 of 175 (34.3%) in the control group (risk difference, −4%; 95% CI, −15% to 6%; P=0.39). The median score on the IES-R was 12 in the intervention group and 13 in the control group (difference, −1.47; 95% CI, −1.93 to 4.87; P=0.38). The researchers found no significant difference between the intervention group and the control group for any of the prespecified secondary outcomes.

The researchers noted four possible explanations for the intervention's failure to reduce PTSD symptoms, including that patients read their diaries a median of only three times, that the delivery of the diary might have been suboptimal, that reading an ICU diary can be a stressful experience in itself, and that patients in the study were not considered at high risk for PTSD. They also noted that PTSD symptoms and symptoms of anxiety and depression were not evaluated at baseline and that some of the diaries were not sufficiently detailed, among other limitations. They concluded that ICU diaries did not significantly reduce PTSD symptoms at three months among patients receiving mechanical ventilation in the ICU and that use of such diaries for preventing these symptoms is not supported.

An editorial accompanying both studies noted that flexible visitation may not have increased family members' involvement sufficiently to affect patient outcomes and that interventions to improve psychological outcomes of critically ill patients and family members depend on context. For example, the editorialists said, the flexible visiting hours tested in the first study were considered standard practice in most of the ICUs in the second study. “Although it would be easy to be dismissive of these 2 trials to improve post-ICU outcomes in patients and families because of the statistically nonsignificant primary outcome findings, their results highlight the high risk of poor psychological outcomes and the heterogeneity of the patients and families at risk,” the editorialists wrote.