Syncope, sepsis resuscitation, and more

Research summaries from ACP Hospitalist Weekly.

NT-proBNP values appear unhelpful in predicting syncope outcomes

Adding N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels to an existing ED syncope risk score did not improve prediction of serious adverse events at 30 days, a recent study found.

Researchers in Canada performed a prospective cohort study in adults who presented with syncope at six EDs to determine whether NT-proBNP levels could help improve prediction of 30-day adverse events when added to the Canadian Syncope Risk Score (CSRS). The CSRS consists of nine components, three from the clinical evaluation (predisposition to vasovagal symptoms, history of heart disease, and any systolic blood pressure <90 mm Hg or >180 mm Hg in the ED), four from testing (elevated troponin level >99th percentile for the normal population, abnormal QRS axis below −30 degrees or >100 degrees, QRS duration >130 ms, and corrected QT interval >480 ms), and two ED diagnosis predictors (vasovagal or cardiac syncope). The study's primary outcome was an adjudicated composite outcome of severe adverse events at 30 days, including death and cardiac and noncardiac events. Events were required to be related to the index syncope. Results of the study were published April 28 by Annals of Internal Medicine and appeared in the May 19 issue.

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The study included 1,452 patients with a mean age of 58.1 years; 51.6% were women. One hundred fifty-two patients (10.5% [95% CI, 9.0% to 12.1%]) experienced severe adverse events by 30 days, 95 (6.5%) during their index ED evaluation and 57 (3.9%) afterward. Patients who experienced severe adverse events had significantly higher levels of NT-proBNP versus patients who did not (median, 626.5 ng/L vs. 81 ng/L; P<0.001), but no improvement in prognostication was seen when NT-proBNP values were added to the CSRS (c-statistic, 0.900 with NT-proBNP values vs. 0.892 without; P=0.12 for the difference). This finding persisted regardless of type of severe adverse event and whether the event was noted during or after the index ED visit. Adding NT-proBNP to the CSRS would have correctly reclassified 3% of patients with severe adverse events while incorrectly reclassifying 2% of patients without severe adverse events, according to the net reclassification index.

The authors said that although ED patients with syncope who had a severe adverse event 30 days after presentation had much higher serum levels of NT-proBNP compared with those who did not experience such an event, the test added minimal new information to the CSRS. “Given that the predictive performance of the CSRS is already high for all SAEs [severe adverse events], as well as for cardiac and arrhythmic SAEs . . . and given the limited power and heterogeneity of the conditions included as the study outcomes, it will be challenging for new variables to improve such robust baseline prediction,” the authors wrote. They concluded that routine use of NT-proBNP for ED prognostication of syncope is not recommended.

Dynamic measures to guide fluid resuscitation may improve outcomes in septic shock

Using dynamic assessments of fluid responsiveness to guide fluid resuscitation may help improve outcomes in patients with septic shock, a recent study found.

Researchers in the U.S. and the U.K. performed a randomized trial of patients who presented to EDs at 13 hospitals with sepsis-associated hypotension and who were considered probable candidates for ICU admission. The goal of the study, which was funded by Cheetah Medical, was to examine whether stroke volume-guided dynamic assessment could help determine the amount of IV fluid to give to septic shock patients. Patients in the intervention group were assessed for fluid responsiveness with a passive leg raise before they received a fluid bolus or before vasopressor dose was increased in the first 72 hours of ICU admission, while those in the control group received usual care. Vasopressor and fluid management based on stroke volume was used continuously in the intervention group.

The study's primary clinical end point was positive fluid balance at 72 hours or at ICU discharge, whichever happened first. New requirement for renal replacement therapy, new requirement for mechanical ventilation, length of ICU stay, hours of ventilator use within 30 days, hours with vasopressor use, and change from baseline serum creatinine level were prespecified secondary end points. Results of the trial were published April 27 by CHEST.

One hundred two patients were randomly assigned to the intervention group, and 48 were randomly assigned to the control group. Of these, 83 patients and 41 patients, respectively, were included in a modified intention-to-treat analysis. Mean age was 62.1 years, and there were more women in the intervention group than in the control group (61.4% vs. 31.7%). The results indicated that fluid balance at 72 hours or ICU discharge was significantly lower in the intervention group than in the control group (0.65 L vs. 2.02 L; P=0.021). In addition, renal replacement therapy and mechanical ventilation were required less often in the intervention group (5.1% vs. 17.5% and 17.7% vs. 34.1%, respectively; P=0.04 for both comparisons). No significant between-group difference was seen in length of hospital stay (difference, 1.2 days; 95% CI, −4.70 to 2.25 days) or overall 30-day mortality rate (difference, 6.3%; 95% CI, −21.2% to 8.6%), although more patients in the intervention group were discharged home alive (difference, 20%; 95% CI, 1.6% to 38.3%). In an intention-to-treat analysis of safety end points that included all randomized patients, rates of serious adverse events, major cardiovascular events, and mortality were similar in the intervention and control groups.

The researchers noted that the study was not blinded and was not powered to detect differences in all sepsis-associated organ dysfunction or mortality, among other limitations. They concluded that using stroke volume change induced by passive leg raise to inform fluid and vasopressor resuscitation in patients with septic shock is safe and may result in lower net fluid balance and lower risk for renal and respiratory failure. “Functional evaluation for lack of fluid responsiveness adequately identifies a group of patients with sepsis-associated hypotension that should not have further IV fluids infused,” the authors wrote. “While [passive leg raise]-guided fluid and vasopressor resuscitation did not improve survival in this study, administering IV fluids and vasopressors only when they were likely to improve [cardiac output] did reduce 72-hour fluid balance and improve discharge to home.”

Most inpatients with sepsis did not have antibiotic-resistant pathogens, but two-thirds received broad-spectrum therapy

While broad-spectrum antimicrobial therapy is frequently prescribed in patients hospitalized with culture-positive community-onset sepsis, most patients do not have antibiotic-resistant pathogens, a recent study found.

The cohort study included adult patients admitted to 104 U.S. hospitals between January 2009 and December 2015 with sepsis who had positive clinical cultures within two days of admission. Researchers assessed the prevalence of and empiric treatment for antibiotic-resistant pathogens, as well as outcomes associated with inadequate empiric antibiotic therapy (defined as presence of one or more pathogens not susceptible to all antibiotics administered on the first or second day of treatment) and unnecessarily broad empiric therapy (defined as use of drugs active against methicillin-resistant Staphylococcus aureus [MRSA]; vancomycin-resistant enterococcus [VRE]; ceftriaxone-resistant gram-negative organisms, including Pseudomonas aeruginosa; or extended-spectrum beta-lactamase [ESBL] gram-negative organisms when none of these were isolated). Results were published on April 16 by JAMA Network Open.

Of 17,430 patients with culture-positive community-onset sepsis (median age, 69 years; 55.9% women), 2,865 (16.4%) died in the hospital. The most common culture-positive sites were urine (52.1%), blood (40.0%), and the respiratory tract (16.7%). The most common pathogens were Escherichia coli (33.7%), Staphylococcus aureus (21.3%), and Streptococcus species (13.5%). While 11,683 (67.0%) cases received empiric therapy targeting resistant organisms (primarily vancomycin and anti-Pseudomonal beta-lactams), resistant organisms were uncommon (MRSA, 11.7%; ceftriaxone-resistant gram-negative organisms, 13.1%; VRE, 2.1%; and ESBLs, 0.8%). The net prevalence for at least one resistant gram-positive organism (i.e., MRSA or VRE) was 13.6% (2,376 patients), and for at least one resistant gram-negative organism (i.e., ceftriaxone-resistant gram-negative organisms, ESBL, or CRE), it was 13.2% (2,297 patients). Among 15,183 cases in which all antibiotic-pathogen susceptibility combinations could be calculated, most (81.6%) received adequate empiric antibiotics. After risk adjustment, both inadequate and unnecessarily broad empiric antibiotics were associated with higher mortality (odds ratios, 1.19 [95% CI, 1.03 to 1.37] [P=0.02] and 1.22 [95% CI, 1.06 to 1.40] [P=0.007], respectively). In subgroup analyses, inadequate antibiotic therapy was not associated with in-hospital death among patients with septic shock (odds ratio, 1.10 [95% CI, 0.87 to 1.38]; P=0.44) but was associated with in-hospital death among patients who had positive blood cultures alone (adjusted odds ratio, 1.40 [95% CI, 1.07 to 1.84]; P=0.02).

The study authors noted that the results “almost certainly overestimate the prevalence of resistant pathogens across the entire spectrum of patients treated for possible sepsis” because the analysis was limited to bacterial, culture-positive sepsis. Among other limitations, the study used a convenience sample of hospitals and was not able to calculate the time to antibiotics, an important predictor of patient outcomes, they said.

“These findings underscore the need for better diagnostic tests to rapidly identify resistant pathogens and an increased focus on judicious use of broad-spectrum antibiotics for the empiric treatment of sepsis,” they concluded.

Opioid agonist therapy infrequently prescribed during hospitalization for veterans with opioid use disorder

In-hospital treatment for opioid use disorder (OUD) is rare in Veterans Health Administration (VHA) hospitals, a study found.

Researchers retrospectively assessed patient- and hospital-level characteristics associated with opioid agonist therapy with methadone or buprenorphine during hospitalization at 109 VHA hospitals in the continental U.S. The study included 12,407 adult patients (median age, 61 years; 93% men) with an OUD-related ICD-10 diagnosis in the 12 months prior to or during index hospitalization in fiscal year 2017. Results were published online on April 14 by the Journal of General Internal Medicine and appeared in the August issue.

Overall, 1,914 (15%) patients received opioid agonist therapy during hospitalization. When provided, OUD treatment was most often for withdrawal management (n=834; 44%). Among patients who received opioid agonist therapy, methadone was more common (n=1,049; 55%) than buprenorphine (n=639; 33%). One hundred thirty-six patients (7.1%) received more than one type of opioid agonist therapy, and 4.7% (n=90) had nonspecific administration. Among 1,325 patients receiving opioid agonist therapy prior to admission, 867 (65%) had their therapy continued during admission, and 458 (35%) had their therapy discontinued during admission. Among 10,969 patients who were not on opioid agonist therapy prior to admission and survived hospitalization, 203 (2%) newly initiated opioid agonist therapy with linkage to care after hospital discharge.

Receipt of opioid agonist therapy was more common among patients with preadmission opioid agonist therapy (adjusted odds ratio [OR], 15.30; 95% CI, 13.2 to 17.7), acute OUD diagnosis (adjusted OR, 2.3; 95% CI, 1.99 to 2.66), and male gender (adjusted OR, 1.52; 95% CI, 1.16 to 2.01). Patients who received non-opioid agonist therapy opioids (adjusted OR, 0.53; 95% CI, 0.46 to 0.61) or surgical procedures (adjusted OR, 0.75; 95% CI, 0.57 to 0.99) had decreased odds of receiving opioid agonist therapy. Hospitals varied in the frequency of opioid agonist therapy delivery, ranging from 0% to 43% of qualified admissions. Large (adjusted OR, 2.00; 95% CI, 1.39 to 3.00) and medium (adjusted OR, 1.90; 95% CI, 1.33 to 2.70) hospitals were more likely to provide opioid agonist therapy than small hospitals.

Among other limitations, the findings may not be generalizable to other cohorts and health system settings, and some patients may have been misclassified with an OUD diagnosis and thus were not valid candidates for treatment, the study authors noted. “Unfortunately, our study suggests that hospital [opioid agonist therapy] delivery frequency may be far from optimal,” they wrote. “The current practice is not only a missed opportunity for treatment engagement, but may also cause harm by disrupting life-saving care.”

For patients with injection drug-related invasive infections leaving AMA, oral antibiotic prescription may reduce readmissions

Patients who inject drugs and are hospitalized for invasive infections may have better outcomes if given access to oral antibiotic therapy, a single-center study found.

Researchers at an academic medical center in St. Louis, Mo., performed a retrospective cohort study of adult patients who used injection drugs, who were admitted between January 2016 and July 2019, and who received a consultation with an infectious disease subspecialist for an invasive bacterial or fungal infection. Outcomes were compared via chart review in patients who completed a full course of IV antibiotics during their inpatient stay, received a partial IV course and no antibiotics prescription at discharge against medical advice (AMA), or received a partial IV course and an oral antibiotics prescription at AMA discharge. The study results were published April 2 by Clinical Infectious Diseases.

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Two hundred ninety-three patients were included in the study. Of these, 143 (48.8%) completed inpatient IV antibiotics, 83 (28.3%) completed a partial IV course and left AMA with an oral antibiotic prescription, and 67 (22.9%) completed a partial IV course and left AMA without an oral antibiotic prescription. All-cause readmission rates at 90 days in these three groups were 31.5%, 32.5%, and 68.7%, respectively. A multivariate analysis found that, compared to patients who completed IV antibiotics, those who did not receive oral antibiotic therapy at AMA discharge had a higher 90-day readmission risk (adjusted hazard ratio, 2.32; 95% CI, 1.41 to 3.82), but no difference in risk was seen for those who did receive oral antibiotic therapy (adjusted hazard ratio, 0.99; 95% CI, 0.62 to 1.62). Reduced readmission risk at 90 days was also associated with surgical source control, defined as receiving a surgical procedure for invasive infection (adjusted hazard ratio, 0.57; 95% CI, 0.37 to 0.87), and multidisciplinary management via an addiction medicine consultation (adjusted hazard ratio, 0.57; 95% CI, 0.38 to 0.86).

Limitations of the study included its potential lack of generalizability and the fact that all patients received an infectious disease consultation, which is known to improve outcomes, the authors noted. They concluded that their results support a holistic approach to management for patients who inject drugs, including offering oral antibiotics to those who leave AMA and shared decision making about IV versus oral antibiotics, among other interventions. “We believe that additional studies specifically evaluating the role and impact of health navigators, case managers, therapists and addiction medicine providers are needed to identify key bundle components while containing costs,” the authors wrote.

Troponin level may help predict mortality in patients admitted with afib

Increased troponin level may be associated with risk for death in patients presenting with atrial fibrillation, according to a recent study.

Researchers in the United Kingdom used a national database to identify patients admitted to five tertiary care centers with a primary diagnosis of atrial fibrillation between 2010 and 2017. The goal of the study was to determine the relationship between troponin level and mortality, as well as the role of coronary angiography. Peak troponin level was used for all analyses. During follow-up, patients were categorized as having had angiography or intervention if the procedure was performed within three months of the peak troponin level. Patients were followed until death or censoring on April 1, 2017. The study results were published on March 26 by the Journal of the American Heart Association and appeared in the April 9 issue.

Overall, 3,121 patients were included in the analysis, with a median follow-up of 48.1 months. The mean age was 73 years, and 55.7% were men. Five hundred eighty-six patients (18.8%) died during the follow-up period, with a one-year mortality rate of 4.8%. The adjusted hazard ratio for mortality associated with a positive troponin level, defined as a value above the upper limit of normal, was 1.20 (95% CI, 1.01 to 1.43; P<0.05). An association was seen between a higher troponin level and a higher risk for death, for a maximum hazard ratio of 2.6 (95% CI, 1.9 to 3.4) when troponin levels were approximately 250 multiples of the upper limit of normal. The researchers noted an exponential relationship between higher troponin levels and increased odds of coronary angiography. Patients who had coronary angiography had a lower risk for death than those who did not (adjusted hazard ratio, 0.61; 95% CI, 0.42 to 0.89; P=0.01).

The authors noted that their study was retrospective, included only patients who had a troponin measurement available, and could not determine the effect of troponin on cardiovascular outcomes versus all-cause mortality, among other limitations. However, they concluded that increased troponin levels were associated with an increased risk for death in patients who presented with atrial fibrillation. In addition, they wrote, “the lower hazard ratio in patients undergoing invasive management raises the possibility that the clinical importance of troponin release in [atrial fibrillation] may be mediated by coronary artery disease, which may be responsive to revascularization.” They called for clinical trials to examine the potential role of investigating and treating coronary artery disease in patients with increased troponin levels and atrial fibrillation.

Prediction score identified critically ill patients at increased risk for VTE

A prediction score helped to identify patients in the ICU who were at increased risk for in-hospital symptomatic venous thromboembolism (VTE).

Researchers at a five-hospital health system in Detroit retrospectively reviewed records for all adult patients admitted to any ICU (total of 264 beds) between January 2015 and March 2018. They defined in-hospital symptomatic VTE as acute deep venous thrombosis of the upper or lower extremities, pulmonary embolism, or both diagnosed more than 24 hours after ICU admission and confirmed by ultrasound, CT, or nuclear medicine imaging. They derived a prediction score (the ICU-VTE score) from independent risk factors identified using multivariable logistic regression. Results were published on March 13 by Critical Care Medicine and appeared in the June issue.

A total of 37,050 patients met the eligibility criteria, and 79% received VTE pharmacoprophylaxis. Overall, 529 patients (1.4%) developed symptomatic VTE. The median interval from ICU admission to VTE diagnosis was six days, and most events occurred within the first two weeks of ICU admission. The ICU-VTE score was derived from six independent predictors: central venous catheterization (5 points), immobilization for four days or more (4 points), history of VTE (4 points), mechanical ventilation (2 points), lowest hemoglobin level during hospitalization greater than or equal to 9 g/dL (2 points), and platelet count at admission greater than 250,000 cells/µL (1 point). ICU-VTE scores ranged from 0 to 18 points and were divided into three categories of VTE risk. Patients with a score of 0 to 8 (76% of the sample) had a low (0.3%) risk of VTE, those with a score of 9 to 14 (22%) had an intermediate (3.6%) risk, and those with a score of 15 to 18 (2%) had a high (17.7%) risk. In an internal validation cohort of 11,083 patients, the c-statistic (a measure of accuracy) of the score was 0.86 (95% CI, 0.83 to 0.88), indicating high predictive accuracy and similarity to the entire cohort.

Among other limitations, the study only counted symptomatic VTE and did not include data on VTE events occurring after hospitalization, the study authors said. They added that they did not look at ICU disease severity scores, vasopressor use, or serial prothrombin times as potential risk factors during hospitalization.

The ICU-VTE score can be applied to the full spectrum of medical and surgical critically ill patients, the authors concluded. “Further research should focus on retrospective external validation of the ICU-VTE score in other cohorts, prospective evaluation of score performance after integration into EMR systems, and exploration of how adjunctive testing for hypercoagulability (i.e., with viscoelastic testing) might further improve predictive accuracy,” they said.

Early use of conservative vs. liberal oxygen therapy did not improve ARDS survival, study finds

Patients with acute respiratory distress syndrome (ARDS) may not benefit from early use of conservative oxygen therapy, according to a recent trial.

Researchers in France performed a multicenter randomized trial that assigned ICU patients receiving mechanical ventilation for ARDS to receive conservative oxygen therapy, defined as a target PaO2 of 55 to 70 mm Hg and an oxygen saturation of 88% to 92% on pulse oximetry, or liberal oxygen therapy, defined as a target PaO2 of 90 to 105 mm Hg and an oxygen saturation of 96% or higher on pulse oximetry. The primary outcome of the study was all-cause mortality at 28 days. The data and safety monitoring board stopped the study prematurely due to safety concerns, as well as a low likelihood that the primary outcome would differ significantly between the two groups. Results of the study were published March 12 by the New England Journal of Medicine.

Two hundred five patients were enrolled in the trial before it was stopped. One hundred three patients were randomly assigned to the conservative oxygen group, and 102 were randomly assigned to the liberal oxygen group. After randomization, four patients were excluded because they did not meet the eligibility criteria. The mean age of the remaining patients was approximately 63 years, and 64% were men. Thirty-four of 99 patients in the conservative oxygen group (34.3%) and 27 of 102 patients in the liberal oxygen group (26.5%) had died at 28 days (difference, 7.8 percentage points; 95% CI, −4.8 to 2.06 percentage points), a nonsignificant difference. At 90 days, however, 44.4% and 30.4%, respectively, had died (difference, 14.0 percentage points; 95% CI, 0.7 to 27.2 percentage points). Five mesenteric ischemic events occurred in the conservative oxygen group versus zero in the liberal oxygen group.

In addition to the trial's early termination and other limitations, the authors noted that study investigators were aware of treatment assignment and that the lower oxygen threshold used is difficult to continuously maintain. They concluded that early use of a conservative oxygen strategy in patients with ARDS at a PaO2 between 50 and 70 mm Hg was not associated with improved survival at 28 days. The authors called the possible signal of increased mortality and risk for mesenteric ischemia in the group assigned to lower oxygen “worrisome” but noted that its significance to clinical practice is unclear.

The author of an accompanying editorial referenced a study published Oct. 14, 2019, in the New England Journal of Medicine in which 1,000 adults receiving mechanical ventilation in the ICU received conservative oxygen or usual care. While administration of oxygen difference varied greatly between the two groups, no significant difference was seen in the primary outcome, ventilator-free days, or mortality, and no safety concerns with conservative therapy were noted. The editorialist pointed out key differences between this trial and the current trial: The first enrolled a broad cohort versus only patients with ARDS, targeted a specific oxygen saturation in the control group rather than usual care, and used a higher oxygen saturation target in the conservative strategy group.

“Determining how to use oxygen supplementation in patients undergoing oxygen supplementation remains an important question, but it requires more nuance than first anticipated,” the editorialist concluded. He called for future trials to examine how targets are set and achieved and how the consequences of such targets affect different patients and different types of organ injuries. “In the meantime, avoiding excess oxygen (i.e., not administering supplemental oxygen when the [oxygen saturation] is 96% or greater and not starting supplemental oxygen when the [oxygen saturation] is 92% or 93%) seems sensible, as per recent guidelines,” the editorialist wrote. However, based on the results of the current trial, he suggested 90% versus 88% as the lower target range for oxygen saturation.