Effect of heparin treatment on pulmonary embolism and in-hospital death in unvaccinated COVID-19 patients without overt deep vein thrombosis.

BACKGROUND: Pulmonary embolism (PE) without overt deep vein thrombosis (DVT) was common in hospitalized coronavirus-induced disease (COVID)-19 patients and represented a diagnostic, prognostic, and therapeutic challenge. The aim of this study was to analyze the prognostic role of PE on mortality and the preventive effect of heparin on PE and mortality in unvaccinated COVID-19 patients without overt DVT. METHODS: Data from 401 unvaccinated patients (age 68 ± 13 years, 33% females) consecutively admitted to the intensive care unit or the medical ward were included in a retrospective longitudinal study. PE was documented by computed tomography scan and DVT by compressive venous ultrasound. The effect of PE diagnosis and any heparin use on in-hospital death (primary outcome) was analyzed by a classical survival model. The preventive effect of heparin on either PE diagnosis or in-hospital death (secondary outcome) was analyzed by a multi-state model after having reclassified patients who started heparin after PE diagnosis as not treated. RESULTS: Median follow-up time was 8 days (range 1-40 days). PE cumulative incidence and in-hospital mortality were 27% and 20%, respectively. PE was predicted by increased D-dimer levels and COVID-19 severity. Independent predictors of in-hospital death were age (hazards ratio (HR) 1.05, 95% confidence interval (CI) 1.03-1.08, p < 0.001), body mass index (HR 0.93, 95% CI 0.89-0.98, p = 0.004), COVID-19 severity (severe versus mild/moderate HR 3.67, 95% CI 1.30-10.4, p = 0.014, critical versus mild/moderate HR 12.1, 95% CI 4.57-32.2, p < 0.001), active neoplasia (HR 2.58, 95% CI 1.48-4.50, p < 0.001), chronic obstructive pulmonary disease (HR 2.47; 95% CI 1.15-5.27, p = 0.020), respiratory rate (HR 1.06, 95% CI 1.02-1.11, p = 0.008), heart rate (HR 1.03, 95% CI 1.01-1.04, p < 0.001), and any heparin treatment (HR 0.35, 95% CI 0.18-0.67, p = 0.001). In the multi-state model, preventive heparin at prophylactic or intermediate/therapeutic dose, compared with no treatment, reduced PE risk and in-hospital death, but it did not influence mortality of patients with a PE diagnosis. CONCLUSIONS: PE was common during the first waves pandemic in unvaccinated patients, but it was not a negative prognostic factor for in-hospital death. Heparin treatment at any dose prevented mortality independently of PE diagnosis, D-dimer levels, and disease severity.

Short vs long-course antibiotic therapy in pyelonephritis: a comparison of systematic reviews and guidelines for the SIMI choosing wisely campaign.

BACKGROUND: The Italian Society of Internal Medicine (SIMI) Choosing Wisely Campaign has recently proposed, among its five items, to reduce the prescription of long-term intravenous antibiotics if not indicated. The aim of our study was to assess the available evidences on optimal duration of antibiotic treatment in pyelonephritis through a systematic review of secondary studies. MATERIALS AND METHODS: We searched for all guidelines on pyelonephritis and systematic reviews assessing the optimal duration of antibiotic therapy in this type of infection. We compared the recommendations of the three most cited and recent guidelines on the topic of interest. We extracted data of non-duplicated RCT from the selected systematic reviews and performed meta-analyses for clinical and microbiological failure. A trial sequential analysis (TSA) was also achieved to identify the need for further evidence. RESULTS: We identified 4 systematic reviews, including data from 10 non-duplicated RCTs (1536 patients). The meta-analysis showed a higher rate of clinical cure for short-course antibiotic treatment (RR for clinical failure 0.70, 95% CI [0.53-0.94]). No significant difference in the rate of microbiological failure (RR 1.06, 95% CI [0.75-1.49]) was observed. In terms of clinical cure, the TSA suggests that current evidence is sufficient to consider short course at least as effective as long-course treatment. Selected guidelines recommend considering shorter courses, but do not cite most of the published RCTs. CONCLUSIONS: Short-course antibiotic treatment is at least as effective as longer courses for both microbiological and clinical success in the treatment of acute uncomplicated pyelonephritis.

Understanding the Pathophysiology of COVID-19: Could the Contact System Be the Key?

To date the pathophysiology of COVID-19 remains unclear: this represents a factor determining the current lack of effective treatments. In this paper, we hypothesized a complex host response to SARS-CoV-2, with the Contact System (CS) playing a pivotal role in innate immune response. CS is linked with different proteolytic defense systems operating in human vasculature: the Kallikrein-Kinin (KKS), the Coagulation/Fibrinolysis and the Renin-Angiotensin (RAS) Systems. We investigated the role of the mediators involved. CS consists of Factor XII (FXII) and plasma prekallikrein (complexed to high-molecular-weight kininogen-HK). Autoactivation of FXII by contact with SARS-CoV-2 could lead to activation of intrinsic coagulation, with fibrin formation (microthrombosis), and fibrinolysis, resulting in increased D-dimer levels. Activation of kallikrein by activated FXII leads to production of bradykinin (BK) from HK. BK binds to B2-receptors, mediating vascular permeability, vasodilation and edema. B1-receptors, binding the metabolite [des-Arg9]-BK (DABK), are up-regulated during infections and mediate lung inflammatory responses. BK could play a relevant role in COVID-19 as already described for other viral models. Angiotensin-Converting-Enzyme (ACE) 2 displays lung protective effects: it inactivates DABK and converts Angiotensin II (Ang II) into Angiotensin-(1-7) and Angiotensin I into Angiotensin-(1-9). SARS-CoV-2 binds to ACE2 for cell entry, downregulating it: an impaired DABK inactivation could lead to an enhanced activity of B1-receptors, and the accumulation of Ang II, through a negative feedback loop, may result in decreased ACE activity, with consequent increase of BK. Therapies targeting the CS, the KKS and action of BK could be effective for the treatment of COVID-19.

[Emergency department visits for interpersonal violence injuries in Udine (Friuli Venezia Giulia Region, Northern Italy)]. / Gli accessi al Pronto soccorso dell'Azienda sanitaria universitaria integrata di Udine per traumatismi causati da violenza interpersonale.

OBJECTIVES: to describe frequency, characteristics, and consequences of intentional injuries due to interpersonal violence visited at the Emergency Rooms of Udine and Cividale del Friuli (Friuli Venezia Giulia Region, North-Eastern Italy). DESIGN: analysis of the administrative database of the Emergency Department. SETTING AND PARTICIPANTS: in the two Emergency Departments of Udine and Cividale del Friuli, serving a 250,000-inhabitant area, all the visits due to injuries from interpersonal violence in the years 2015-2017 were analysed. MAIN OUTCOME MEASURES: number of visits because of injuries from interpersonal violence, distribution of demographic characteristics of patients, of characteristics of the events (place of occurrence, mechanism, relation with patient's occupation, involvement of persons known to the victims), of consequences (discharge diagnosis, Emergency Department management times). RESULTS: in three years, 1,741 visits of violence victims were recorded in the Emergency Department of the Udine area; 8.7% of patients were assigned a triage yellow tag and 1.0% a red tag. Almost one third of victims were non-Italian citizens; 14.2% of events were work-related; more than one third occurred in the home; in one third of cases, the aggressor was known to the victim; 96 people were diagnosed with fractures. The average time from start of medical care and Emergency Room discharge ranged from half an hour among white triage tags to more than three hours among yellow tags. More than 100 people experiences more than one violent episode. CONCLUSIONS: this is the first description of frequency, characteristics, and health impact of violence in the area of Udine, providing information useful for a targeted prevention. It also highlights the central role of the Emergency Department not only for the registration of the phenomenon, but also for the management of the acute episodes and for the prevention of recurrent events.

Short- vs long-course antibiotic therapy for pneumonia: a comparison of systematic reviews and guidelines for the SIMI Choosing Wisely Campaign.

Reduction of the inappropriate use of antibiotics in clinical practice is one of the main goals of the Società Italiana di Medicina Interna (SIMI) choosing wisely campaign. We conducted a systematic review of secondary studies (systematic reviews and guidelines) to verify what evidence is available on the duration of antibiotic treatment in Pneumonia. A literature systematic search was performed to identify all systematic reviews and the three most cited and recent guidelines that address the duration of antibiotic therapy in pneumonia. Moreover, a meta-analysis of non-duplicate data from randomized controlled trials (RCTs) considered in the enrolled systematic reviews was performed together with a trial sequential analysis to identify the need for further studies. Two systematic reviews on antibiotic duration in community-acquired pneumonia (CAP) for a total of 17 RCTs (2764 patients) were enrolled in our study. Meta-analysis of non-duplicate RCTs show a non-significant difference in rate of treatment failure between short (≤ 7 days) and long (> 7 days) antibiotic treatment course: RR 1.05 (95% CI, 0.82-1.36). The trial sequential analysis suggests that further data would not affect current evidence or become clinically relevant. Selected guidelines suggest consideration of a short course, with a low grade of evidence and without citing the already published systematic reviews. Antibiotic treatment of CAP for ≤ 7 days is not associated with a higher rate of treatment failure than longer courses and should thus be taken in consideration. Guidelines should upgrade the evidence on this topic.

Major bleeding with vitamin K antagonists or direct oral anticoagulants in real-life.

BACKGROUND: Limited data are available on major bleeding (MB) occurring during treatment with vitamin K (VKAs) or direct oral anticoagulants (DOACs) outside clinical trials. METHODS: Patients hospitalized for MB while on treatment with VKAs or DOACs were included in a multicenter study to compare clinical presentation, management and outcome of bleeding. The primary study outcome was death at 30days. RESULTS: Between September 2013 and September 2015, 806 patients were included in the study, 76% on VKAs and 24% on DOACs. MB was an intracranial hemorrhage in 51% and 21% patients on VKAs or DOACs, respectively (Odds Ratio [OR] 3.79; 95% confidence interval [CI] 2.59-5.54) a gastrointestinal bleeding in 46% and 25% patients on DOACs and VKAs, respectively (OR 2.62; 95% CI 1.87-3.68). Death at 30days occurred in 130 patients (16%), 18% and 9% of VKA and DOAC patients (HR 1.95; 95% CI 1.19-3.22, p=0.008). The rate of death at 30days was similar in VKA and DOAC patients with intracranial hemorrhage (26% and 24%; HR 1.05, 95% CI 0.54-2.02) and gastrointestinal bleeding (11% and 7%; HR 1.46, 95% CI 0.57-3.74) and higher in VKA than DOAC patients with other MBs (10% and 3%; HR 3.42, 95% CI 0.78-15.03). CONCLUSIONS: Admission for ICH is less frequent for DOAC patients compared with VKA patients. Admission for gastrointestinal MB is more frequent for DOAC as compared to VKA patients. Mortality seems lower in patients with MBs while on DOACs than VKAs but this finding varies across different types of MBs.

The Italian Society of Internal Medicine choosing wisely campaign.

Appropriateness is one of the critical aspects of medicine. For this reason, the Italian Society of Internal Medicine (SIMI) decided to adhere to the Choosing Wisely Campaign. A bottom-up approach was chosen. All the recommendations published in the US and Canadian Choosing Wisely campaign have been screened, and an e-mail was sent to all the SIMI members for new suggestions. The thirty interventions that were judged as the highest priority by a committee were sent to all the SIMI members for voting. The first procedures selected were then revised, and constituted the five points of the SIMI choosing wisely campaign. The identified procedures were: (1) avoid prescribing bed rest unless an acceptable indication exists. Promote early mobilization; (2) Do not perform a D-dimer test without a precise indication; (3) Do not prescribe long term intravenous antibiotic therapy in the absence of symptoms; (4) Do not indefinitely prescribe proton pump inhibitors in the absence of specific indications; (5) Do not place, or leave in place, peripherally inserted central catheters for patient's or provider's convenience. Four of these points were not present in any other campaign, while one, the fifth, was already present. The bottom-up approach of the SIMI "Choosing Wisely" campaign favored the identification of different priorities compared to other campaigns. Future studies should now evaluate if the application of these "not-to-do" recommendations will be associated with an improvement of clinical outcome and a subsequent direct and indirect health care cost reduction.

Low-back pain at the emergency department: still not being managed?

BACKGROUND: Low-back pain (LBP) affects about 40% of people at some point in their lives. In the presence of "red flags", further tests must be done to rule out underlying problems; however, biomedical imaging is currently overused. LBP involves large in-hospital and out-of-hospital economic costs, and it is also the most common musculoskeletal disorder seen in emergency departments (EDs). PATIENTS AND METHODS: This retrospective observational study enrolled 1,298 patients admitted to the ED, including all International Classification of Diseases 10 diagnosis codes for sciatica, lumbosciatica, and lumbago. We collected patients' demographic data, medical history, lab workup and imaging performed at the ED, drugs administered at the ED, ED length of stay (LOS), numeric rating scale pain score, admission to ward, and ward LOS data. Thereafter, we performed a cost analysis. RESULTS: Mean numeric rating scale scores were higher than 7/10. Home medication consisted of no drug consumption in up to 90% of patients. Oxycodone-naloxone was the strong opioid most frequently prescribed for the home. Once at the ED, nonsteroidal anti-inflammatory drugs and opiates were administered to up to 72% and 42% of patients, respectively. Imaging was performed in up to 56% of patients. Mean ED LOS was 4 hours, 14 minutes. A total of 43 patients were admitted to a ward. The expense for each non-ward-admitted patient was approximately €200 in the ED, while the mean expense for ward-admitted patients was €9,500, with a mean LOS of 15 days. CONCLUSION: There is not yet a defined therapeutic care process for the patient with LBP with clear criteria for an ED visit. It is to this end that we need a clinical pathway for the prehospital management of LBP syndrome and consequently for an in-hospital time-saving therapeutic approach to the patient.

Reducing the risk of hospital admission: a call to action from the Italian Society of Internal Medicine.

The belief that hospital stays may constitute per se a risk for patients is not widespread among patients and health care professionals. In the balance between advantages and disadvantages of admission, we rarely take into account the impact of the hospital stay itself on the well-being of the patient. In a society that is getting older the hospital may become a hostile environment for the complex and frail patient. Reducing the risks associated with hospital admission implies a radical cultural change accepted and shared by all health care professionals. The critical reconsideration of admission is a way of reasoning not only on hospitalisation but also on what the correct health outcome paradigms should be.

Implementation of a Meningitis Care Bundle in the Emergency Room Reduces Mortality Associated With Acute Bacterial Meningitis.

BACKGROUND: Prompt administration of antibiotics, adjunctive steroid therapy, and optimization of antibiotic delivery to cerebrospinal fluid (CSF) are factors associated with improved outcome of patients hospitalized for acute bacterial meningitis (ABM). However, the impact of a bundle of these procedures has not been reported. OBJECTIVE: To assess mortality and neurological sequelae at hospital discharge in a cohort of patients with ABM managed according to a predefined bundle. METHODS: Prospective study of all the patients hospitalized for ABM in two provinces of Northern Italy, over two consecutive periods (2005-2009, 2010-2013). The bundle included: i) supportive care if needed; ii) immediate administration of dexamethasone and 3rd generation cephalosporin; and iii) addition of levofloxacin if turbid CSF. Patients managed according to the bundle were compared with a historical group of patients cared for ABM before the bundle was implemented. RESULTS: Overall, 85 patients with ABM were managed according to the bundle and were compared with 92 historical controls. In-hospital mortality rates for bundle and control group were 4.7% and 14.1% (p=0.04). Among survivors, 13.5% and 18.9% (p=0.4) of bundle and control-group patients presented neurological sequelae. The only variable associated with mortality at multivariate analysis was ICU admission (HR 3.65). After adjusting for ICU admission, patients managed according with the ABM bundle had significantly lower mortality rate compared to historical controls. CONCLUSIONS: Use of a bundled protocol and antibiotics with excellent CSF penetration for the initial management of ABM in emergency department is feasible and associated with significant reduction in mortality.

"What, diagnosis?" Between Bayes and biases.

I conducted a personal survey, completely informal, asking groups of doctors during training courses to give me in writing, in a strictly anonymous fashion, a brief operative description of diagnosis. The majority were unfocused and confusing regarding the process and nobody mentioned any probability-based criteria. Objectively, diagnosis is a difficult concept and rich with implications: this is the heart of medical activity and few doctors are able to define it correctly. There exist well-founded reasons to ask ourselves what diagnosis means and how many are the implications and the many environments in which the concept might be declined. We have to accept that even at the end of a complete and exhaustive diagnostic workup, it might not be possible to reach a diagnosis and it is much wiser to admit it rather than giving the patient a label that will abandon them only with extreme difficulty. Whether or not we like it, we behave, even unconsciously, like convinced Bayesians and we should be aware of the fact that the predictive value of your test will vary on how high or low is the presence of the illness. With a very low prevalence, even a very sensitive test might produce an unacceptably high number of false positives. Naturally, it is not necessary to supply a definition of diagnosis to be a good doctor. What counts is that we are aware that the diagnostic process is based on probability and not certainty, we are prone to biases, diagnostic tests can have false positives and false negatives, and having reached a certain threshold of probability and trust in diagnosis we should decide, with our patients, what to do or not do.

TDM-guided therapy with daptomycin and meropenem in a morbidly obese, critically ill patient.

OBJECTIVE: To describe a case of severe cellulitis, successfully treated with high-dose daptomycin plus continuous infusion meropenem, in a patient with morbid obesity and renal failure, in whom drug exposure over time was optimized by means of real-time therapeutic drug monitoring (TDM). CASE SUMMARY: A 63-year-old man with morbid obesity (body mass index 81.6 kg/m²) and renal failure was admitted to the emergency department because of severe cellulitis. The patient had an admission Laboratory Risk Indicator for Necrotizing Fasciitis score of 9, and broad-spectrum antimicrobial therapy with daptomycin and meropenem was started. Because of rapidly changing renal function, dosage adjustments were guided by an intensive program of TDM (daptomycin ranging from 1200 mg every 48 hours over 30 minutes to 1200 mg every 36 hours over 30 minutes; meropenem ranging from 0.25 g every 8 hours over 6 hours to 500 mg every 4 hours by continuous infusion). Clinical response was observed within 72 hours. However, a sudden increase of serum creatine kinase (SCK) raised questions about the need for discontinuation of daptomycin. The drug concentrations were not toxic; therefore, we decided to continue therapy. Significant clinical improvement, with SCK normalization, was observed within a few days. Antimicrobial therapy was switched on day 29 to amoxicillin/clavulanate plus levofloxacin, and then discontinued at discharge on day 53. DISCUSSION: High-dose daptomycin plus continuous infusion meropenem may ensure adequate empiric antimicrobial coverage in patients with possible early necrotizing fasciitis. However, in patients with morbid obesity and changing renal function, significant challenges may arise because of the hydrophilic nature of these drugs and the inaccuracy of standard methods of estimating renal function. CONCLUSIONS: Real-time TDM may represent an invaluable approach in optimizing drug exposure with high-dose daptomycin plus continuous infusion meropenem in patients with severe cellulitis, morbid obesity, and changing renal function.

A case-crossover study of sleep and work hours and the risk of road traffic accidents.

STUDY OBJECTIVES: Sleepiness, prolonged wakefulness, and extended work hours have been associated with increased risk of injuries and road accidents. The authors' objective was to study the relation between those factors and road accidents using a case-crossover design, effective in estimating the risk of acute events associated with transient, short effect exposures. DESIGN: Five hundred seventy-four injured drivers presenting for care after road accidents to the Emergency Room of Udine, Italy, were enrolled in the study from March 2007 to March 2008. Sleep, work, and driving patterns in the 48 h before the accident were assessed through an interview. MEASUREMENTS AND RESULTS: The relative risk (RR) of accident associated with each exposure was estimated using the case-crossover matched pair interval approach. Sleeping > or = 11 h daily was associated with a decrease of the RR, as was sleeping less than usual. Being awake > or = 16 h and, possibly, working > 12 h daily were associated with increases in the RR. CONCLUSIONS: Extended work hours and prolonged wakefulness increase the risk of road accidents and suggest that awareness should be raised among drivers. The findings regarding acute sleep amount are less clear, possibly due to an effect of chronic sleep loss.

A case-crossover study of alcohol consumption, meals and the risk of road traffic crashes.

BACKGROUND: The case-crossover (CC) design has proved effective to investigate the association between alcohol use and injuries in general, but has never been applied to study alcohol use and road traffic crashes (RTCs) specifically. This study aims at investigating the association between alcohol and meal consumption and the risk of RTCs using intrapersonal comparisons of subjects while driving. METHODS: Drivers admitted to an Italian emergency room (ER) after RTCs in 2007 were interviewed about personal, vehicle, and crash characteristics as well as hourly patterns of driving, and alcohol and food intake in the 24 hours before the crash. The odds ratio (OR) of a RTC was estimated through a CC, matched pair interval approach. Alcohol and meal consumption 6 and 2 hours before the RTC (case exposure window) were compared with exposures in earlier control windows of analogous length. RESULTS: Of 574 patients enrolled, 326 (56.8%) reported previous driving from 6 to 18 hours before the RTC and were eligible for analysis. The ORs (mutually adjusted) were 2.25 (95%CI 1.11-4.57) for alcohol and 0.94 (0.47-1.88) for meals. OR for alcohol was already increased at low (1-2 units) doses - 2.17 (1.03-4.57) and the trend of increase for each unit was significant - 1.64 (95%CI 1.05-2.57). In drivers at fault the OR for alcohol was 21.22 (2.31-194.79). The OR estimate for meal consumption seemed to increase in case of previous sleep deprivation, 2.06 (0.25-17.00). CONCLUSION: Each single unit of acute alcohol consumption increases the risk of RTCs, in contrast with the 'legal' threshold allowed in some countries. Meal consumption is not associated with RTCs, but its combined effects with sleepiness need further elucidation.

[Chest pain evaluation project]. / Percorso di valutazione del dolore toracico. Valutazione dei requisiti di base per l'implementazione negli ospedali italiani.

The evaluation of acute chest pain remains challenging, despite many insights and innovations over the past two decades. The percentage of patients presenting at the emergency department with acute chest pain who are subsequently admitted to the hospital appears to be increasing. Patients with acute coronary syndromes who are inadvertently discharged from the emergency department have an adverse short-term prognosis. However, the admission of a patient with chest pain who is at low risk for acute coronary syndrome can lead to unnecessary tests and procedures, with their burden of costs and complications. Therefore, with increasing economic pressures on health care, physicians and administrators are interested in improving the efficiency of care for patients with acute chest pain. Since the emergency department organization (i.e. the availability of an intensive observational area) and integration of care and treatment between emergency physicians and cardiologists greatly differ over the national territory, the purpose of the present position paper is two-fold: first, to review the evidence-based efficacy and utility of various diagnostic tools, and, second, to delineate the basic critical pathways (describing key steps for care and treatment) that need to be implemented in order to standardize and expedite the evaluation of chest pain patients, making their diagnosis and treatment as uniform as possible across the country.

Unusual extension of an intracardiac primary lymphoma to the right jugular vein.

We report an unusual case of a 61-year-old woman with right atrial primary cardiac lymphoma extending into the right jugular vein through the superior vena cava. A transoesophageal echocardiographic study revealed the presence of a large mass occupying four fifths of the right atrial cavity and invading the superior vena cava, which appeared almost completely occluded. These findings were confirmed by computed tomography scan and magnetic resonance imaging. At autopsy, a large (7 x 3 cm) whitish ovoid mass with multiple nodules was found in the right atrium and superior vena cava. Histopathological examination revealed a monotonous population of lymphoid B-cells.

[Effectiveness of retraining after basic cardiopulmonary resuscitation courses: a literature review]. / L'andamento delle performance e l'efficacia del retraining dopo il primo corso di rianimazione cardiopolmonare di base: revisione della letteratura.

Cardiopulmonary resuscitation (CPR) is one of the compulsory skills for health care professionals. Health professionals (and lay people) are offered CPR courses to learn this skill that may be implemented after a long time. Is a course enough to learn and retain this skill? Are retraining courses effective? And after how long should retraining courses be offered? These are some of the questions that guided the search of the literature. Three database were searched (medline, cinahl and healthstar) with the key-words cardiopulmonary resuscitation, retention skills, psychomotor performance, refresh course and retraining and the references of the articles were manually searched to identify further articles. After the exclusion of the articles on pediatric and advanced resuscitation and whose objective was the evaluation of the effectiveness of teaching methods 8 studies were finally identified. No clear indications are proposed. Resuscitations skills deteriorate quickly and theoretical knowledge is retained longer than practical skills. The retraining should be offered frequently but no time intervals are proposed. The main suggestion is that no standard approach should be adopted and the learning needs and preferences of the learner should be considered.