Thursday, August 31, 2017

Digoxin use for atrial fibrillation and mortality

Methods and Results In the ENGAGE AF‐TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation‐Thrombolysis in Myocardial Infarction 48) trial, clinical outcomes of patients with atrial fibrillation with and without HF were examined by baseline digoxin use during a median follow‐up of 2.8 years. HF was defined at baseline as prior or current clinical stage C or D HF. Of 21 105 patients enrolled, 6327 (30%) were treated with digoxin at baseline. Among patients without HF (n=8981), digoxin use (20%) was independently associated with sudden cardiac death (adjusted hazard ratio, 1.51; 95% CI, 1.10–2.08), with no significant interaction by age, sex, left ventricular ejection fraction, renal function, or concomitant medications (P greater than 0.05 for each). Consistent results were observed using propensity matching (adjusted hazard ratio for sudden cardiac death, 1.90; 95% CI, 1.36–2.65). Among patients with HF (n=12 124), digoxin use (37%) was associated with an increase in all‐cause death, cardiovascular death, sudden cardiac death, and death caused by HF/cardiogenic shock (P less than 0.01 for each), but not with noncardiovascular death, stroke/systemic embolism, or myocardial infarction.

Conclusions In this observational analysis of patients with atrial fibrillation without investigator‐reported HF, digoxin use was significantly associated with sudden cardiac death. While residual confounding cannot be excluded, the association between digoxin use and worse clinical outcomes highlights the need to examine digoxin use, particularly when prescribed to control heart rate in patients with atrial fibrillation in a randomized trial.

Tuesday, August 29, 2017

DIC in sepsis

Here are some key points from a recent review. The review is available as free full text.

DIC is characterized by activation of procoagulant factors (with an important role of tissue factor expression from activated monocytes and endothelial cells) and down regulation of natural anticoagulants and fibrinolytics (protein C, plasminogen activator and others).

Thus, while clotting may dominate the picture early on clotting factors are consumed, moving the picture toward the bleeding end of the clinical spectrum. At the point of patient presentation either side of the spectrum may dominate, and often both do.

The spectrum of severity is quite variable.

From the article:

Sepsis is almost invariably associated with coagulation abnormalities. These deviations range from delicate activation of coagulation that can only be identified by highly sensitive assays for coagulation factor activation to somewhat more severe hemostatic activation that may be noticeable by a subtle fall in platelet count and sub-clinical elongation of global clotting assays to fulminant disseminated intravascular coagulation (DIC), manifested by widespread microvascular thrombosis in small and mid-size vessels and simultaneous profuse hemorrhage from various sites [[4], [5]]. Patients with sepsis and extensive forms of DIC may develop overt thrombo-embolic complications or clinically less apparent microvascular clot formation that may contribute to multiple organ failure [[5], [6]]. In other cases, severe hemorrhage may be the dominant presentation [7], and frequently sepsis and DIC leads to simultaneous thrombosis and bleeding. Hemorrhage is due to consumption and subsequent depletion of coagulation factors and platelets, caused by ongoing activation of the hemostatic system [8]. In its most extreme manifestation this combination may present as the Waterhouse-Friderichsen syndrome, typically observed during fulminant meningococcal septicemia, although many other microorganisms may cause this clinical situation as well [9].

How often is sepsis accompanied by DIC?

Some degree of coagulation disturbance is present in virtually all patients but it may be subclinical. According to the article 50-70% of patients will have clinically relevant coagulation changes and about 35% will meet criteria for DIC. (Published criteria for overt DIC and non overt DIC are based on scoring systems and are found here).

A drop in platelets occurs in almost all patients with sepsis and the mechanisms are multiple and complex.

From the article:

The vast majority of patients with sepsis will develop thrombocytopenia (platelet count less than 150 × 109/l) [[11], [12]]. Commonly, platelet count drops in the first four days following admission to the hospital [13]. The severity of sepsis correlates strongly with the decrease in platelet count [14]. Crucial factors that cause thrombocytopenia in sepsis are decreased platelet production, enhanced consumption, obliteration, or sequestration in the spleen. Impaired production of megakaryocytes in the bone marrow may seem incongruous with the high levels of platelet production-stimulating pro-inflammatory mediators, such as tumor necrosis factor (TNF)-α and interleukin (IL)-6, and elevated levels of thrombopoietin in patients with sepsis, which theoretically should stimulate megakaryopoiesis [15]. However, in a large number of patients with sepsis substantial hemophagocytosis occurs, consisting of active phagocytosis of platelet precursors and other hematopoietic cells by mononuclear cells, presumably caused by elevated concentrations of macrophage colony stimulating factor (M-CSF) in sepsis [16]. Platelet consumption is presumably also important in sepsis, due to platelet activation secondary to continuous formation of thrombin.

Monday, August 28, 2017

Desmopressin spray approved for nocturnal polyuria

Sunday, August 27, 2017

Follow up ultrasound and D dimer testing to help guide the duration of anticoagulation for DVT



The optimal long-term strategy for preventing recurrent venous thromboembolism (VTE) in patients with deep-vein thrombosis (DVT) is uncertain.

In 620 consecutive outpatients with a first proximal DVT who had completed at least three months of anticoagulation (unprovoked in 483, associated with minor risk factors in 137), the ultrasound presence of residual vein thrombosis (RVT) was assessed and defined as an incompressibility of at least 4 mm. In 517 patients without RVT and with negative D-dimer, anticoagulation was stopped and D-dimer was repeated after one and three months. Anticoagulation was resumed in 63 of the 72 patients in whom D-dimer reverted to positivity.


During a mean follow-up of three years, recurrent VTE developed in 40 (7.7%) of the 517 patients, leading to an annual rate of 3.6% (95% CI, 2.6 to 4.9): 4.1% (95% CI, 2.9 to 5.7) in individuals with unprovoked DVT, and 2.2% (95% CI, 1.1 to 4.5) in those with DVT associated with minor risk factors. Of the 233 males with unprovoked DVT, 17 (7.3%) developed events in the first year of follow-up. Major bleeding complications occurred in 8 patients while on anticoagulation, leading to an annual rate of 1.2% (95% CI, 0.6 to 2.4).


Discontinuing anticoagulation in patients with a first episode of proximal DVT based on the assessment of RVT and serial D-dimer leads to an overall annual rate of recurrent VTE lower than 5.0%, which is the rate deemed as acceptable by the Subcommittee on Control of Anticoagulation of the ISTH. However, in males with unprovoked DVT there is room for further improving the long-term strategy of VTE prevention.

The current Chest guidelines raise similar concerns about men and recommend against the use of D dimer guidance in men.

Monday, August 14, 2017

When can one discontinue non invasive positive pressure ventilation in severe COPD exacerbation?


We assessed whether prolongation of nocturnal noninvasive ventilation (NIV) after recovery from acute hypercapnic respiratory failure (AHRF) in chronic obstructive pulmonary disease (COPD) patients with NIV could prevent subsequent relapse of AHRF.

A randomised controlled trial was performed in 120 COPD patients without previous domiciliary ventilation, admitted for AHRF and treated with NIV. When the episode was resolved and patients tolerated unassisted breathing for 4 h, they were randomly allocated to receive three additional nights of NIV (n=61) or direct NIV discontinuation (n=59). The primary outcome was relapse of AHRF within 8 days after NIV discontinuation.

Except for a shorter median (interquartile range) intermediate respiratory care unit (IRCU) stay in the direct discontinuation group (4 (2–6) versus 5 (4–7) days, p=0.036), no differences were observed in relapse of AHRF after NIV discontinuation (10 (17%) versus 8 (13%) for the direct discontinuation and nocturnal NIV groups, respectively, p=0.56), long-term ventilator dependence, hospital stay, and 6-month hospital readmission or survival.

Prolongation of nocturnal NIV after recovery from an AHRF episode does not prevent subsequent relapse of AHRF in COPD patients without previous domiciliary ventilation, and results in longer IRCU stay. Consequently, NIV can be directly discontinued when the episode is resolved and patients tolerate unassisted breathing.

NIV can be directly discontinued when a COPD exacerbation is resolved and patients tolerate unassisted breathing

Thursday, August 10, 2017

Atrial fibrillation onset in ICU patients

Objective: To determine the association of new-onset atrial fibrillation with outcomes, including ICU length of stay and survival.

Design: Retrospective cohort of ICU admissions. We found atrial fibrillation using automated detection (greater than or equal to 90 s in 30 min) and classed as new-onset if there was no prior diagnosis of atrial fibrillation. We identified determinants of new-onset atrial fibrillation and, using propensity matching, characterized its impact on outcomes.

Setting: Tertiary care academic center.

Patients: A total of 8,356 consecutive adult admissions to either the medical or surgical/trauma/burn ICU with available continuous electrocardiogram data.

Interventions: None.

Measurements and Main Results: From 74 patient-years of every 15-minute observations, we detected atrial fibrillation in 1,610 admissions (19%), with median burden less than 2%. Most atrial fibrillation was paroxysmal; less than 2% of admissions were always in atrial fibrillation. New-onset atrial fibrillation was subclinical or went undocumented in 626, or 8% of all ICU admissions. Advanced age, acute respiratory failure, and sepsis were the strongest predictors of new-onset atrial fibrillation. In propensity-adjusted regression analyses, clinical new-onset atrial fibrillation was associated with increased hospital mortality (odds ratio, 1.63; 95% CI, 1.01–2.63) and longer length of stay (2.25 d; CI, 0.58–3.92). New-onset atrial fibrillation was not associated with survival after hospital discharge (hazard ratio, 0.99; 95% CI, 0.76–1.28 and hazard ratio, 1.11; 95% CI, 0.67–1.83, respectively, for subclinical and clinical new-onset atrial fibrillation).

Conclusions: Automated analysis of continuous electrocardiogram heart rate dynamics detects new-onset atrial fibrillation in many ICU patients. Though often transient and frequently unrecognized, new-onset atrial fibrillation is associated with poor hospital outcomes.

Tuesday, August 01, 2017

Antibiotic associated adverse events in hospitalized patients

Importance Estimates of the incidence of overall antibiotic-associated adverse drug events (ADEs) in hospitalized patients are generally unavailable.

Objective To describe the incidence of antibiotic-associated ADEs for adult inpatients receiving systemic antibiotic therapy.

Design, Setting, and Participants Retrospective cohort of adult inpatients admitted to general medicine wards at an academic medical center.

Exposures At least 24 hours of any parenteral or oral antibiotic therapy.

Main Outcomes and Measures Medical records of 1488 patients were examined for 30 days after antibiotic initiation for the development of the following antibiotic-associated ADEs: gastrointestinal, dermatologic, musculoskeletal, hematologic, hepatobiliary, renal, cardiac, and neurologic; and 90 days for the development of Clostridium difficile infection or incident multidrug-resistant organism infection, based on adjudication by 2 infectious diseases trained clinicians.

Results In 1488 patients, the median age was 59 years (interquartile range, 49-69 years), and 758 (51%) participants were female. A total of 298 (20%) patients experienced at least 1 antibiotic-associated ADE. Furthermore, 56 (20%) non–clinically indicated antibiotic regimens were associated with an ADE, including 7 cases of C difficile infection. Every additional 10 days of antibiotic therapy conferred a 3% increased risk of an ADE. The most common ADEs were gastrointestinal, renal, and hematologic abnormalities, accounting for 78 (42%), 45 (24%), and 28 (15%) 30-day ADEs, respectively. Notable differences were identified between the incidence of ADEs associated with specific antibiotics.

Conclusions and Relevance Although antibiotics may play a critical role when used appropriately, our findings underscore the importance of judicious antibiotic prescribing to reduce the harm that can result from antibiotic-associated ADEs.