Oral Midodrine Administration During the First 24 Hours of Sepsis to Reduce the Need of Vasoactive Agents: Placebo-Controlled Feasibility Clinical Trial.

Our preliminary data and observational studies suggested an increasing "off label" use of oral midodrine as a vasopressor sparing agent in various groups of critically ill patients, including those with sepsis. We designed this clinical trial to evaluate the feasibility of use of midodrine hydrochloride in early sepsis to reduce the duration for IV vasopressors and decrease ICU and hospital length of stay. DESIGN: Pilot, two-center, placebo-controlled, double blinded randomized clinical trial. SETTING: Medical ICUs at Mayo Clinic Rochester and Cleveland Clinic Abu Dhabi were the study sites. PATIENTS AND METHODS: Adult patients (≥ 18 yr old) were included within 24 hours of meeting the Sepsis-3 definition if the mean arterial pressure remained less than 70 mm Hg despite receiving timely antibiotics and initial IV fluid bolus of 30 cc/kg. INTERVENTION: Three doses of 10 mg midodrine versus placebo were administered. MEASUREMENTS AND MAIN RESULTS: Total 32 patients were randomized into midodrine (n = 17) and placebo groups (n = 15). There were no major differences in baseline variables between the groups except for higher baseline creatinine in the midodrine group (2.0 ± 0.9 mg/dL) versus placebo group (1.4 ± 0.6 mg /dL), p = 0.03. The median duration of IV vasopressor requirement was 14.5 ± 8.1 hours in midodrine group versus 18.8 ± 7.1 hours in the placebo group, p value equals to 0.19. Patients in the midodrine group needed 729 ± 963 norepinephrine equivalent compared with 983 ± 1,569 norepinephrine equivalent in the placebo group, p value equals to 0.59. ICU length of stay was 2.29 days (interquartile range, 1.65-3.9 d) in the midodrine group, compared with 2.45 days (interquartile range, 1.6-3.2 d) in the placebo group, p value equals to 0.36. No serious adverse events were observed in either group. CONCLUSIONS: Phase II clinical trial powered for clinical outcomes (duration of vasopressor use, need for central venous catheter, and ICU and hospital length of stay) is justified.

Special Article - Acute myocardial injury in patients hospitalized with COVID-19 infection: A review.

The Coronavirus Disease 2019 (COVID-19) is now a global pandemic with millions affected and millions more at risk for contracting the infection. The COVID-19 virus, SARS-CoV-2, affects multiple organ systems, especially the lungs and heart. Elevation of cardiac biomarkers, particularly high-sensitivity troponin and/or creatine kinase MB, is common in patients with COVID-19 infection. In our review of clinical analyses, we found that in 26 studies including 11,685 patients, the weighted pooled prevalence of acute myocardial injury was 20% (ranged from 5% to 38% depending on the criteria used). The plausible mechanisms of myocardial injury include, 1) hyperinflammation and cytokine storm mediated through pathologic T-cells and monocytes leading to myocarditis, 2) respiratory failure and hypoxemia resulting in damage to cardiac myocytes, 3) down regulation of ACE2 expression and subsequent protective signaling pathways in cardiac myocytes, 4) hypercoagulability and development of coronary microvascular thrombosis, 5) diffuse endothelial injury and 'endotheliitis' in several organs including the heart, and, 6) inflammation and/or stress causing coronary plaque rupture or supply-demand mismatch leading to myocardial ischemia/infarction. Cardiac biomarkers can be used to aid in diagnosis as well as risk stratification. In patients with elevated hs-troponin, clinical context is important and myocarditis as well as stress induced cardiomyopathy should be considered in the differential, along with type I and type II myocardial infarction. Irrespective of etiology, patients with acute myocardial injury should be prioritized for treatment. Clinical decisions including interventions should be individualized and carefully tailored after thorough review of risks/benefits. Given the complex interplay of SARS-CoV-2 with the cardiovascular system, further investigation into potential mechanisms is needed to guide effective therapies. Randomized trials are urgently needed to investigate treatment modalities to reduce the incidence and mortality associated with COVID-19 related acute myocardial injury.

Concomitant Aspirin and Anticoagulation Is Associated With Increased Risk for Major Bleeding in Surgical Patients Requiring Postoperative Intensive Care.

OBJECTIVES: Critically ill surgical patients may receive concomitant aspirin and therapeutic anticoagulation postoperatively, yet the safety of this practice remains unknown. We evaluated the risk of major bleeding with concomitant therapy compared with anticoagulation alone. DESIGN: Observational cohort study. Inverse probability of treatment weighting was used to assess the association between concomitant therapy and a primary outcome of major bleeding. SETTING: Postoperative ICUs at an academic medical center. PATIENTS: Adults (≥ 18 yr old) receiving anticoagulation during postoperative ICU admission between 2007 and 2016. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Nine thousand five hundred eighteen anticoagulated patients were included, including 3,237 (34%) receiving aspirin. A total of 1,874 unique patients (19.7%) experienced a major bleeding event. In inverse probability of treatment weighting analyses, concomitant therapy was associated with increased odds for major bleeding (odds ratio, 1.20; 95% CI, 1.05-1.36; p = 0.006) compared with anticoagulation alone. An interaction test suggested a differential relationship between aspirin use and major bleeding based on aspirin use in the 7 days prior to anticoagulation, such that a strong association between aspirin and major bleeding was observed for recent initiators of aspirin (1.40; 1.13-1.72;p = 0.002) but not for those continuing prior aspirin use. Aspirin use prior to anticoagulation did not modify the relationship between concomitant therapy and new myocardial infarction or stroke (i.e., rates were not increased with aspirin discontinuation prior to anticoagulation). CONCLUSIONS: Concomitant aspirin and anticoagulation in critically ill surgical patients was associated with an increased rate of major bleeding. Future investigations are warranted to further define optimal management of antiplatelet therapy during anticoagulation in surgical patients.

Risk of major bleeding associated with aspirin use in non-surgical critically ill patients receiving therapeutic anticoagulation.

BACKGROUND: We aimed to evaluate the risk of major bleeding in non-surgical critically ill patients who received aspirin in conjunction with therapeutic anticoagulation (concomitant therapy) compared to those who received therapeutic anticoagulation alone. METHODS: This is a retrospective cohort study of critically ill patients initiated on therapeutic anticoagulation at a large academic medical center from 2007 to 2016. The exposure of interest was aspirin therapy during anticoagulation. The primary outcome was the incidence of major bleeding during hospitalization. Secondary outcomes included in-hospital mortality, hospital free days, and new myocardial infarction or stroke. RESULTS: 5507 (73.2%) patients received anticoagulation alone and 2014 (26.8%) received concomitant therapy; major bleeding occurred in 19.0% and 22.2%, respectively. There was no increased risk of major bleeding [OR 1.10 (95% CI: 0.93-1.30); p = .27] or mortality [OR 0.93 (95% CI: 0.77-1.11); p = .43] with concomitant therapy. Patients receiving concomitant therapy had fewer hospital-free days (mean decrease of 0.73 [1.36, 0.09]; p = .03) and were more likely to experience new myocardial infarction or stroke [OR 2.61 (95% CI: 1.72-3.98); p < .001]. CONCLUSIONS: In non-surgical critically ill patients receiving therapeutic anticoagulation, concomitant use of aspirin was not associated with an increased risk of bleeding or in-hospital mortality.

Etiologies and predictors of 30-day readmissions in patients undergoing percutaneous mechanical circulatory support-assisted percutaneous coronary intervention in the United States: Insights from the Nationwide Readmissions Database.

BACKGROUND: Patients undergoing percutaneous mechanical circulatory support (pMCS)-assisted percutaneous coronary intervention (PCI) represent a high-risk group vulnerable to complications and readmissions. HYPOTHESIS: Thirty-day readmissions after pMCS-assisted PCI are common among patients with comorbidities and account for a significant amount of healthcare spending. METHODS: Patients undergoing PCI and pMCS (Impella, TandemHeart, or intra-aortic balloon pump) for any indication between January 1, 2012, and November 30, 2014, were selected from the Nationwide Readmissions Database. Patients were identified using appropriate ICD-9-CM codes. Clinical risk factors and complications were analyzed for association with 30-day readmission. RESULTS: Our analysis included 29 247 patients, of which 4535 (15.5%) were readmitted within 30 days. On multivariate analysis, age ≥ 65 years, female sex, hypertension, diabetes, chronic lung disease, heart failure, prior implantable cardioverter-defibrillator, liver disease, end-stage renal disease, and length of stay ≥5 days during index hospitalization were independent predictors of 30-day readmission. Cardiac etiologies accounted for ~60% of readmissions, of which systolic or diastolic heart failure (22%), stable coronary artery disease (11.1%), acute coronary syndromes (8.9%), and nonspecific chest pain (4.0%) were the most common causes. In noncardiac causes, sepsis/septic shock (4.6%), hypotension/syncope (3.2%), gastrointestinal bleed (3.1%), and acute kidney injury (2.6%) were among the most common causes of 30-day readmissions. Mean length of stay and cost of readmissions was 4 days and $16 191, respectively. CONCLUSIONS: Thirty-day readmissions after pMCS-assisted PCI are common and are predominantly associated with increased burden of comorbidities. Reducing readmissions for common cardiac etiologies could save substantial healthcare costs.

Trends in Use of Midodrine in the ICU: A Single-Center Retrospective Case Series.

OBJECTIVES: Midodrine is an oral alpha-agonist approved for orthostatic hypotension. The use of midodrine as a vasopressor sparing agent has steadily increased in the ICU despite limited evidence for its safety in that setting. We describe the trends in use and reported side effects and complications of midodrine in multidisciplinary ICUs of a tertiary care institution. DESIGN: Single-center retrospective case series. SETTING: Medical and surgical ICU patients from January 2011 to October 2016 at Mayo Clinic, Rochester. PATIENTS: Adult patients admitted to any ICU who received midodrine for hypotension were eligible. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We reviewed the mean arterial pressures and cumulative vasopressor dose before and after midodrine administration and assessed for reported complications. During the study period, a total of 1,119 patients were initiated on midodrine, 56% in surgical ICUs, 42% in medical ICUs, and 2% in a mixed medical and surgical neurology ICU. There was a significant decrease in the number of patients on vasopressors 24 hours after initiation of midodrine (663 to 344; p < 0.001); among the patients that remained on vasopressors, there was a significant decrease in the median cumulative vasopressor dose (p = 0.002). There was a significant increase in median mean arterial pressure 24 hours after initiation of midodrine among patients who were not on vasopressors (65-68; p < 0.01). Asymptomatic bradycardia (heart rate < 50 beats/min) was the most common side effect (n = 172 patients, median 39 beats/min). Two patients developed bowel ischemia after initiation of midodrine that prompted discontinuation of midodrine in one case. Evaluating trends of utilization, the off-label use of midodrine has increased steadily over the years across ICUs. CONCLUSIONS: Our results suggest that midodrine is being increasingly used as an adjunct to increase mean arterial pressure and facilitate weaning of vasopressors in the ICU. Prospective trials are required to further establish the appropriate timing, efficacy, safety, and cost-effectiveness of midodrine use in ICU patients.

Impact of Obesity on Outcomes in a Multiethnic Cohort of Medical Intensive Care Unit Patients.

PURPOSE: To examine the association of obesity with in-hospital mortality and complications during critical illness. METHODS: We performed a retrospective analysis of a multiethnic cohort of 699 patients admitted to medical intensive care unit between January 2010 and May 2011 at Mount Sinai St. Luke's and Mount Sinai West Hospitals, tertiary care centers in New York City. Multivariate logistic regression analysis was used to evaluate the association between obesity (body mass index [BMI] ≥ 30] and in-hospital mortality. Subgroup analysis was performed in elderly patients (age ≥65 years). RESULTS: Compared to normal BMI, obese patients had lower in-hospital mortality (24.4% vs 17.6%, P = .04). On multivariate analysis, obesity was independently associated with lower in-hospital mortality (odds ratio [OR]: 0.49, 95% confidence interval [CI]: 0.27-0.89, P = .018). There was no significant difference in rates of mechanical ventilation, reintubation, and vasopressor requirement across BMI categories. In subgroup analysis, elderly obese patients did not display lower in-hospital mortality (adjusted OR: 0.85, 95% CI: 0.40-1.82, P = .68). CONCLUSION: Our study supports the hypothesis that obesity is associated with decreased mortality during critical illness. However, this finding was not observed among elderly obese patients. Further studies should explore the interaction between age, obesity, and outcomes in critical illness.

Duration of Dual Antiplatelet Therapy in Patients with an Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention.

BACKGROUND: The recent American Heart Association/American College of Cardiology guidelines on duration of dual antiplatelet therapy (DAPT) recommend DAPT for 1 year in patients presenting with an acute coronary syndrome, with a Class IIb recommendation for continuation. We aim to assess the evidence for these recommendations using a meta-analytic approach. METHODS: We searched electronic databases for randomized trials comparing short-term (≤6 months) vs 12-month vs extended (>12 months) DAPT in patients with an acute coronary syndrome undergoing percutaneous coronary intervention. We evaluated all-cause mortality, cardiovascular mortality, myocardial infarction, stent thrombosis, and major bleeding. A random-effects model was used to calculate pooled relative risk (RR) and 95% confidence intervals (CI). RESULTS: We included 8 trials comprising 12,917 patients with an acute coronary syndrome; 5 trials compared short-term vs 12-month/extended DAPT, whereas 3 trials compared 12-month vs extended DAPT. There was no significant difference in cardiovascular mortality (RR 1.04; 95% CI, 0.67-1.60), myocardial infarction (RR 1.08; 95% CI, 0.79-1.47), or major bleeding (RR 0.91; 95% CI, 0.49-1.69) between short-term and 12-month/extended DAPT. However, compared with extended DAPT, 12-month DAPT showed significantly higher risk of myocardial infarction (RR 2.00; 95% CI, 1.47-2.73), but reduced risk of major bleeding (RR 0.58; 95% CI, 0.34-0.98). All-cause mortality was found to be similar between 12-month and extended DAPT. CONCLUSIONS: In acute coronary syndrome, short-term DAPT may be reasonable for some patients, whereas extended DAPT may be appropriate in select others. An individualized approach is needed, taking into account the competing risks of bleeding and ischemic events.

Occupational asthma: diagnostic challenges and management dilemmas.

PURPOSE OF REVIEW: Work-related asthma encompasses both sensitizer-induced and irritant-induced occupational asthma as well as work-exacerbated asthma. This review summarizes current diagnostic and management strategies for occupational asthma. RECENT FINDINGS: Occupational asthma is the most common occupational lung disease in the industrialized world. Over 400 agents have been described to cause occupational asthma. Specific inhalation challenge is often considered the reference method for diagnosis of occupational asthma but specific inhalation challenge as well as other diagnostic tests all generate false positive or false negative results. Definitive avoidance of the inciting agent is the preferred strategy for sensitizer-induced occupational asthma and reduction of exposure is the next best step. Immunotherapy is not currently well established and can cause systemic reactions. SUMMARY: An accurate diagnosis made in a timely fashion can positively impact the health and socioeconomic burden associated with occupational asthma. Newer diagnostic tools are promising, but much work needs to be done to standardize and validate these testing methods. Primary, secondary, and tertiary prevention strategies are crucial for effective management of sensitizer-induced occupational asthma.

Meta-Analysis of Randomized Trials on the Efficacy and Safety of Angiotensin-Converting Enzyme Inhibitors in Patients ≥65 Years of Age.

The comparative efficacy and safety of angiotensin-converting enzyme inhibitors (ACEIs) with other agents in patients ≥65 years of age with cardiovascular diseases or at-risk are unknown. Electronic databases were systematically searched to identify all randomized controlled trials that compared ACEIs with control (placebo or active) and reported long-term cardiovascular outcomes. We required the mean age of patients in the studies to be ≥65 years. Random-effects model was used to pool study results. Sixteen trials with 104,321 patients and a mean follow-up of 2.9 years were included. Compared with placebo, ACEIs significantly reduced all outcomes except stroke. Compared with active controls, ACEIs had similar effect on all-cause mortality (relative risk [RR] 0.99, 95% confidence interval [CI] 0.95 to 1.03), cardiovascular mortality (RR 0.99, 95% CI 0.93 to 1.04), heart failure (RR 0.97, 95% CI 0.91 to 1.03), myocardial infarction (RR 0.94, 95% CI 0.88 to 1.00), and stroke (RR 1.07, 95% CI 0.99 to 1.15). ACEIs were associated with an increased risk of angioedema (RR 2.79, 95% CI 1.05 to 7.42), whereas risk for hypotension and renal insufficiency was similar compared with active controls. Meta-regression analysis showed that the effect of ACEIs on outcomes remained consistent with age increasing ≥65 years. Sensitivity analysis excluding trials comparing ACEIs with angiotensin receptor blockers and heart failure trials yielded similar results, except for reduction in myocardial infarction. In conclusion, the efficacy of ACEIs was similar to active controls for mortality outcomes. Compared with placebo, there was evidence for reduction in cardiovascular outcomes; however, ACEIs failed to prevent stroke and increased the risk of angioedema, hypotension, and renal failure.

Short and long-term mortality in women and men undergoing primary angioplasty: A comprehensive meta-analysis.

INTRODUCTION: Women with acute myocardial infarction are treated less aggressively than men and have a higher mortality. It is possible that these sex-related differences in outcome are a result of differences in baseline risk and management. METHODS AND RESULTS: We undertook a meta-analysis to study the differences in mortality among women and men with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (P-PCI). Studies reporting sex-specific crude mortality rates and/or adjusted effect estimates in STEMI patients undergoing P-PCI were identified. Among 48 studies, involving 103,895 patients, (26,556 women and 77,337 men), the crude in-hospital [pooled relative risk (RR): 1.94, 95% confidence interval (CI): 1.74-2.16, p<0.001; 23 studies (n=43,872)], 30-day [RR: 1.76, 95% CI: 1.50-2.07, p<0.001; 20 studies (n=43,279)], and long-term [RR: 1.60, 95% CI: 1.46-1.76, p<0.001; 26 studies (n=51,656)] mortality was significantly higher in women compared to men. When meta-analysis using adjusted effect estimates from individual studies was performed, in-hospital [RR: 1.31, 95% CI: 1.08-1.65, p=0.007; 14 studies (n=33,380)] and 30-day mortality [RR: 1.19, 95% CI: 1.01-1.39, p=0.03; 14 studies (n=28,564)] remained significant while long-term mortality [RR: 1.01, 95% CI: 0.93-1.11, p=0.75; 20 studies (n=52,492)] was no longer different between women and men. CONCLUSIONS: Sex-based differences exist in short and long-term mortality among patients with STEMI undergoing P-PCI. However, these differences were markedly attenuated following adjustment for clinical differences and/or hospital course. Despite adjustment, short-term mortality remains higher in women than men, while long-term mortality was no longer significantly different.

Impact of obesity on sepsis mortality: A systematic review.

PURPOSE: Sepsis and severe sepsis are the most common cause of death among critically ill patients admitted in medical intensive care units. As more than one-third of the adult population of the United States is obese; we undertook a systematic review of the association between obesity and mortality among patients admitted with sepsis, severe sepsis, or septic shock. MATERIALS AND METHODS: A systematic review was conducted to identify pertinent studies using a comprehensive search strategy. Studies reporting mortality in obese patients admitted with sepsis were identified. RESULTS: Our initial search identified 183 studies of which 7 studies met our inclusion criteria. Three studies reported no significant association between obesity and mortality, 1 study observed increased mortality among obese patients, whereas 3 studies found lower mortality among obese patients. CONCLUSION: Our review of the current clinical evidence of association of obesity with sepsis mortality revealed mixed results. Clinicians are faced with a number of challenges while managing obese patients with sepsis and should be mindful of the impact of obesity on antibiotics administration, fluid resuscitation, and ventilator management. Further studies are needed to elicit the impact of obesity on mortality in patients with sepsis.