Moderate Bleeding Research Articles

Predictive factors associated with outcome in patients six months after mild to moderate aneurysmal subarachnoid hemorrhage: Focus on neuropsychological tests conducted one month after the event

ObjectiveThe study aimed to investigate predictive factors associated with outcome six months after mild to moderate aneurysmal subarachnoid hemorrhage (SAH). MethodsWe divided 136 patients (51 men and 85 women) after SAH (Hunt & Kosnik [H&K] grade I to III) into groups with good and poor outcome according to scores on the modified Rankin Scale (mRS) at six months after SAH onset: good outcome (mRS score, 0–1; n = 105) and poor outcome (mRS score, 2–6; n = 31). At admission, we assessed age, sex, H&K grade, and Fisher grade, and one month after aneurysmal SAH, we evaluated aneurysm location, treatment modality (coil embolization, clipping, or no surgical treatment), proportion of patients who underwent shunt placement, proportion of patients with delayed cerebral ischemia, and scores on neuropsychological tests (Mini-Mental State Examination, Raven’s Colored Progressive Matrices, Kana-hiroi Test, Trail Making Test, and Rey-Osterrieth Complex Figure Test, immediate recall). ResultsH&K grade was associated with outcome (χ2 = 6.220, P = 0.005), and a significantly higher proportion of the good outcome group had an H&K grade II (P = 0.025). The good outcome group had significantly better scores on the Mini-Mental State Examination (U = 1251, P = 0.045), Raven’s Colored Progressive Matrices (U = 1224, P = 0.036), and Trail Making Test parts A (U = 1238, P = 0.043) and B (U = 1247, P = 0.048). However, we found no significant intergroup differences in the other patient demographic and disease characteristics, including age, treatment modality, and delayed cerebral ischemia, or in the other neuropsychological assessments. Binary logistic regression analysis identified H&K grade I and II as predictive factors associated with good outcome. ConclusionBesides severity at admission as indicated by H&K grade, neuropsychological tests explicitly performed one month after mild to moderate aneurysmal SAH may help nursing staff to predict patient outcome, including possible symptoms after discharge.

The Sensitivity and Specificity of Rotational Thromboelastometry (ROTEM) to Detect Coagulopathy During Moderate and Severe Postpartum Hemorrhage: A Prospective Observational Study

(Int J Obstet Anes. 2022;49:103238) Viscoelastometric hemostatic assays, such as rotational thromboelastometry (ROTEM), offer rapid, point-of-care identification of coagulopathy during postpartum hemorrhage (PPH). Previous studies investigating the use of ROTEM have used a Delta ROTEM device. This study investigates the use of the ROTEM Sigma device, identifying the sensitivity, specificity, and positive or negative predictive values in patients with PPH.

Eptacog Beta Efficacy in Treating Mild or Moderate Bleeds in Target Joints of Individuals with Hemophilia A or B and Inhibitors in PERSEPT 1

Introduction Recurrent bleeding in the same joint of a patient with hemophilia can lead to painful and chronic inflammation of the synovium, joint swelling, reduced range of motion, and in the long term joint arthropathy and irreversible joint damage. Early bleed resolution in the susceptible joint (known as a target joint) is thought to be crucial for preventing joint arthropathy and other incapacitating sequelae, and thus ultimately preserving joint function and health in persons with hemophilia. Eptacog beta was FDA-approved in 2020 as a recombinant activated human factor VII for the treatment and control of bleeding episodes (BEs) in persons with hemophilia A or B and inhibitors (PwHABI) ages 12 years and older using two initial dose regimens (IDRs) of 75 or 225 µg/kg eptacog beta that were shown to be safe and efficacious. The pivotal phase 3 trial (PERSEPT 1; NCT02020369) included 27 PwHABI ages 12 to 54 years who treated 465 mild or moderate BEs, with treatment success proportions at 12 hours post-initial infusion of 82% and 91% for 75 and 225 µg/kg IDRs, respectively. Objective To evaluate eptacog beta efficacy when treating target and non-target joint BEs in PwHABI from PERSEPT 1, at 12 and 24 hours post-initial dose of eptacog beta. Methods PERSEPT 1 was a global, multicenter, open-label, prospective phase 3 trial using a crossover design (Wang et al., Haemophilia 23, pp. 832-43 [2017]). PwHABI who were not using prophylaxis were randomized to either the 75 or the 225 µg/kg IDR to treat BEs, and were crossed over to the alternate IDR every 3 months. Subjects in the 75 µg/kg IDR treated BEs with initial doses of 75 µg/kg eptacog beta followed by 75 µg/kg q3h as needed. Subjects in the 225 µg/kg IDR treated BEs with an initial 225 µg/kg eptacog beta dose, followed after 9 hours by 75 µg/kg q3h as needed. Mild or moderate BE treatment success at a given timepoint was defined as obtaining a hemostasis evaluation of "excellent" or "good" on a 4-point scale ("excellent" or "good" indicating hemostatic efficacy; "moderate" or "none" indicating lack of efficacy) with no additional eptacog beta being infused, no alternative hemostatic agents or blood products being used, and no increase in pain following the first "excellent" or "good" assessment. A target joint was defined in this trial as a joint in which recurrent bleeding had occurred on 4 or more occasions during the previous 6 months, or a joint in which 20 lifetime BEs had occurred. Results Twenty-seven PwHABI treated 396 mild or moderate joint BEs in PERSEPT 1; 17 of these subjects had been previously diagnosed with target joints. Of the 396 mild or moderate joint BEs treated, 135 were target joint bleeds (in 15 subjects) and 261 were non-target joint bleeds (in 25 subjects). At 12 hours post-initial infusion, target joint treatment success proportions and 95% confidence intervals (CIs) were 82% (95% CI: [63%, 100%]) and 93% (95% CI: 82%, 100%]) in the 75 and 225 µg/kg IDRs, respectively (Figure 1). Corresponding success proportions and CIs for non-target joint bleeds were 86% (95% CI: [75%, 97%]) and 95% (95% CI: [90%, 100%]), respectively. The increase in treatment success proportion observed at 12 hours with the 225 µg/kg IDR over the 75 µg/kg IDR was statistically significant for both target joint and non-target joint groups (p < 0.05). For both IDRs, the difference in treatment success proportions between target and non-target joint BEs was not statistically significant. Nearly all target (97-100%) and non-target joint bleeds (96-100%) were successfully treated at 24 hours post-initial eptacog beta infusion in each IDR (Figure 1). Conclusions The increase in both target and non-target joint bleed treatment success seen at 12 hours for the 225 µg/kg IDR over the 75 µg/kg IDR was statistically significant, and is consistent with a dose-dependent thrombin burst driving effective clot formation at the site of injury. While the 75 µg/kg IDR may be appropriate for certain patients, the 225 µg/kg IDR shows improved treatment success at 12 hours and may be the preferred choice in most circumstances. With the high efficacy seen at 24 hours, eptacog beta offers an important treatment option for treating both target and non-target joint BEs in PwHABI. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Thalidomide and Sucralfate Reduce Gastrointestinal Bleeding in Adults with Hereditary Hemorrhagic Telangiectasia: The Mexican Experience

Introduction Hereditary hemorrhagic telangiectasia (HHT) is the second most common inherited bleeding disorder, occurring in 1/5,000 to 1/10,000 persons. Has an autosomal dominant transmission and can occur de novo. Telangiectases occurs at characteristics sites: lips, oral cavity, fingers and nose; but visceral lesions are common, affecting gastrointestinal tract (GIT), liver, lung, brain and spinal arteriovenous formations. Nosebleed and GIT can lead to iron deficiency anemia. HHT is an underrecognized disease and delay in diagnose can increase morbidity and mortality as more telangiectases develop with aging. Thalidomide treatment for moderate and severe bleedings, that are defined by requirements of intravenous iron replacement and/or transfusions, has been used since more than a decade with good results (Blood 2021;137:888-895 and Hematology Am Soc Educ Program 2021;1:469-477). Material and methods Anemic adults with HHT based in Curaçao clinical diagnosis criteria, three to four from: a) telangiectases, b) epistaxis, c) visceral involvement and d) direct family history (Am J Med Genet 2009;91:66-67); and positive endoscopic study with moderate to severe GIT bleeding; some patients had a full body CT Scan and showed telangiectasi in al GIT as in Figure 1, the bone window reveal fill blooded telangiectasia. Thalidomide was initiated at 100 mg daily for a month and increased to 200 mg daily if tolerated for 12 months; aspirin 100 mg daily for thrombosis prevention; and omeprazole 20 mg with sucralfate 1 gr twice a day for GIT mucosal protection; transfusion to maintain hemoglobin level at 7-8 g/L and iron carboxymaltose to increase Hb levels and maintain ferritin above 50 ng/mL End points before and after treatment: a) number of episodes of GIT bleeding, b) number of red blood cells transfusions, and c) hemoglobin levels. Results Fifteen patients were included, 9 men and 6 females. Age from 28 to 74 years, median 56. All patients tolerated thalidomide 200 mg daily with minimum side effects and no hematologic toxicity, and completed 12 months period. The number episodes per month of GIT bleeding for all the group before treatment were 28, all patients have at least one monthly episode and two patients more than three; after three months and until end of treatment the number of episodes per month reduced to 5 for all the group. The number of red blood cells transfusion for all the group before treatment were 65 units per month, after three months of treatment reduced to 9 units and at end of treatment to 4 units. The mean of Hb level before treatment were 5.86 g/L, after three months of treatment were 9.2 g/L, and at end of treatment were 11.7 g/L. As a secondary observation the nosebleed episodes were reduced to zero after three months of treatment, from 9 episodes before treatment. No thrombotic complications were observed. Median time to increase the GIT bleeding was 9 months after end of treatment. Discussion In HHT, GIT bleeding is a common symptom in older adults over than 50 years due many factors: nosebleed had received various lines of treatment, ageing of the GIT mucosa that leads to the development of more telangiectases and use of medications for chronic diseases, among others. In this case thalidomide with sucralfate are tolerated and have very good results diminishing the GIT bleeding and the red blood cells transfusions, allowing to increase the Hb levels using IV iron. The response is observed in the three first months of treatment and is maintained until nine months after the end of it. Thalidomide as antiangiogenic and Sucralfate as a local healing substance are useful as an option in this kind of patients in low income countries because Bevacizumab, Pomalidomide and other antiangiogenics are more expensive. More trials using thalidome alone or in combination would help to have strong data in results and improve the quality of life of these patients. Finally, after ellectronic search this is the only Mexican experience in the treatment of HHT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Repeated Testing Unfolds the Challenge of Diagnosing Von Willebrand Disease: Longitudinal Data from the Vienna Bleeding Biobank

Background: Diagnosis of von Willebrand disease (VWD) in patients with a mild to moderate bleeding tendency (mild bleeding disorders, MBD) bears special challenges, as von Willebrand factor (VWF) levels are influenced by several factors, such as age, acute phase reaction and blood group, and might be unstable. Unstable VWF levels might lead to under- or over-diagnosis of VWD in MBD patients, and repeated measurements to identify VWD patients might be required. Aims: We aimed to identify clinical and epidemiological factors associated with unstable VWF levels, leading to change of the diagnosis based on the recommended diagnostic cut-off levels. Furthermore, we wanted to investigate cut-off of baseline VWF levels with a low probability to decrease below the diagnostic cut-off and, thus, not require subsequent VWF measurements. Methods: All patients enrolled into the Vienna bleeding biobank (VIBB, EC no. 603/2009) before October 2021 with at least two separate assessments of VWF levels, in particular VWF antigen (VWF:Ag) and activity (VWF:GPIbM and/or ristocetin-cofactor activity [VWF:RCo]), were included in this analysis. Detailed inclusion and exclusion criteria of the VIBB, a single-center cohort study on patients with MBD, have been published previously (Gebhart et al. Haemophilia.2018). For this analysis, pathological VWF levels were defined as any measurement of VWF:Ag, VWF:GPIbM or VWF:RCo ≤50 IU/dL, according to current guidelines (James et al. Blood Adv. 2021). We defined 3 subgroups of patients according to lowest VWF (VWF:Ag or VWF:GPIbM or VWF:RCo) at baseline and at each measurement: patients with steadily pathological measurements ≤50 IU/dL ("steady pathological"), patients with repeatedly normal measurements >50 IU/dL ("steady normal") and patients crossing the 50 IU/dL threshold between study visits ("changing"). Measurements were excluded from the analysis if an evident VWF influence such as pregnancy, infection, surgery or acute phase reaction was identified. Results: In total, 281 of 691 patients (40.7 %) from the VIBB study who had records of at least two VWF measurements of VWF antigen and activity levels were included in this analysis. Patients had a median number of 2 VWF measurements (Q1-Q3, 2-2) over a median follow-up time of 781 days (Q1-Q3, 105-1679) for a total of 660 measurements. 212 patients had 2 measurement of VWF antigen and activity, followed by 3 (n=47), 4 (n=11), 5 (n=5) and 6 (n=1) measurements. Of all analyzed patients, 217 patients (77.2 %) had VWF levels consistently above the cut-off of 50 IU/dL ( "steady normal"), 28 patients (10.0%) had repeatedly values ≤50 IU/dL ("steady pathological"), while 36 patients (12.8%) had changing results with values both below and above the cut-off of 50 IU/dL ( "changing"; Figure 1). The clinical and laboratory characteristics of each subgroup are summarized in Table 1. Patients in the "steady pathological” and "changing” groups compared to the "steady normal” group were younger and more commonly had blood group O. The values of VWF activity (VWF:RCo or VWF:GPIbM) at inclusion appeared to be more unstable than the VWF:Ag values (Figure 1). Seventeen (47.2%) patients in the changing group had pathological VWF activity values but VWF:Ag values above the cut-off of 50 IU/dL at study inclusion. VWF antigen and activity values at baseline within the changing group ranged from 36 IU/dL to 101 IU/dL and 28 IU/dL to 86 IU/dL, respectively. In a logistic regression model, modeling changing status as a binary outcome and lowest VWF at baseline using linear splines with a knot set at 50 IU/dL, the probability of changing was 37.2% (95%CI, 25.7-50.3), 18.6% (95%CI, 12.2-27.4) and 1.1% (95%CI, 0.2-4.8) at 40, 60 and 80 IU/dL, respectively (Figure 2). The added value of the clinical predictors age, sex, the Vicenza score and blood type O beyond lowest VWF at baseline, however, was only weak (χ2 5.0, p = 0.290). Conclusion: Based on our data, the reproducibility of VWF measurements is poor in patients with MBD. Re-evaluation of suspected patients for VWD who do not clearly fulfill the diagnostic criteria should be considered, especially if VWF levels are close to the cut-off level, as targeted treatment before surgical interventions might be warranted. Further studies are needed to better understand the reproducibility of VWF measurements and improve the diagnosis of VWD in patients with MBD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Factor VIII Mimetic Rescue of Hemophilia B Causing Factor IX Variants

Background The intrinsic Xase enzyme complex is responsible for the rate-limiting step of sustained coagulation. It is composed of the protease, activated coagulation factor IX (FIXa), and the cofactor, FVIIIa, bound on phospholipid membranes; deficiencies in the activity of the intrinsic Xase result in hemophilia B (HB) or hemophilia A (HB), respectively. The FVIII-mimetic emicizumab has been widely adopted for prophylaxis for HA patients, in part because of the convenience of subcutaneous administration. Prophylaxis for HB patients, however, still requires frequent intravenous FIX administration. Within the Xase, complex, FVIIIa binding allosterically activates FIXa and enhances FX substrate binding, though the molecular details of the FVIIIa/FIXa interaction remain incompletely understood. We hypothesize that the hemostatic activity of select HB-causing mutations due to dysfunctional FVIIIa/FIXa interactions may be rescuable by FVIII-mimetics such as emicizumab. Aims To determine the spectrum of HB-causing missense FIX variants that have rescuable procoagulant activity with FVIII-mimetics and clarify the interaction between FIXa and FVIIIa at an amino acid level. Methods Recombinant FIX variants were expressed from transiently transfected HEK293 cells. Procoagulant activity of recombinant FIX variant and patient samples were assayed by either aPTT assay, one-stage FIX activity, thrombin generation assay (TGA), and rotation thromboelastography (ROTEM). Results The ability of the FVIII-mimetic emicizumab to rescue the procoagulant activity of HB-causing FIX variants was screened using a modified one-stage FIX activity assay. To account for the high clotting activity of emicizumab in aPTT-based assays, the FIX activity of the HB-causing variants was compared against the activity of wild-type (WT) FIX in the presence of an equal concentration of emicizumab. FVIII-mimetic rescuable HB-causing variants were selected if their activity relative-to-FIX-WT increased at least twofold with the addition of emicizumab. About 20% of FIX variants evaluated to-date appear to be rescuable with emicizumab, including K5E, L6S, D47E, D332Y, R333Q, R338P, P368T, E387G, E387K, and I397T. To further define the procoagulant rescue of these FIX variants, the amount of thrombin generated by these FIX variants in HB plasma was measured with and without emicizumab and compared to FIX-WT with the same emicizumab concentrations. Representative thrombograms are shown in the Figure. The addition of emicizumab increased the peak thrombin generation of the rescuable HB-causing variants 2-6 fold relative-to-FIX-WT. In contrast, emicizumab had no effect on the amount of thrombin generated by the catalytically inert FIX-S365A (S195A in chymotrypsin numbering). We also obtained samples from two moderate HB patients with the I397T missense variant; these patients have between 1-3% normal FIX activity and a moderate bleeding phenotype. We observed that emicizumab could normalized the prolonged aPTT of their plasma and improved the ROTEM clot time of their whole blood in a dose-dependent manner. Conclusions The procoagulant activity of select HB-causing missense FIX variants can be rescued with therapeutics amounts of emicizumab. These variants likely have a dysfunctional interaction with FVIIIa cofactor, which is circumvented in the presence of a FVIII-mimetic. Importantly, such rescuable variants are identified throughout the FIXa protein, highlighting the range of amino acids involved in the FIXa/FVIIIa interaction. Identified rescuable variants likely has dysfunctional FVIIIa-binding (K5E, L6S) and/or disturbed allosteric activation (E387K, I397T). FVIII mimetics may be an alternative prophylactic hemostatic therapy for HB patients with such rescuable variants. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Balancing the Bleeding Risk & Treatment Related Complications in Immune Thrombocytopenia - an Unmet Need: Real-World Data from India

Background: Primary Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder due to decreased platelet count (PLT). Patients (Pts) with ITP face manifold challenges owing to the multifarious burden of living with the disease and its treatment-related complications. Corticosteroids used as first-line therapy in both adults and children do not improve quality of life or patient-related outcomes. The real-world experience data on the treatment outcomes of ITP pts in India is sparse. Objective: Our study aims to compare and evaluate the treatment outcomes and treatment-related adverse events in newly diagnosed ITP pts treated with corticosteroids (Prednisolone/ Dexamethasone) in terms of initial response at 4 weeks (wks) and sustained response at 3 months from initiation of therapy respectively. Methods: We enrolled 73 pts with new onset ITP, attending the outpatient department of AIIMS Rishikesh, between March 2019 to August 2020. Pre-treatment Complete Blood Count(CBC) Platelet count (PLT), Reticulocyte count, LDH, Liver and Renal Function Tests, PT, APTT, ANA, HIV, HBsAg, HCV, USG Abdomen, and Chest X-Ray were done. Bone marrow aspirate and biopsy (BM) was done in pts >50 yrs or to look for other hematological disorders. BM done in 19pts was normal. All pts had a pretreatment PLT <30 x 109/L. Children (age <12yrs) were treated only in the presence of bleeding. The severity of bleeding was graded as per the WHO bleeding score. Pts were randomized by block randomization and treated with Prednisolone or Dexamethasone. Prednisolone was administered at 1mg/kg/day for 4 wks (age >12yrs) and 2mg/kg/day for 2 wks (age < 12yrs) and tapered gradually over 2 months. Dexamethasone was administered at 40mg/day for 4 days/cycle, for 3 cycles at an interval of 14 days. Pts were followed up every wk for the first 4 wks and monthly thereafter for 3 months with CBC, PLT, and evaluated for any possible bleeding/complications. Response was defined as Complete response (CR) plt ≥ 100 x 109 /L. Response (R) plt ≥ 30 x 109/L and >2 fold increase in plt from baseline, no bleeding. No response (NR) plt < 30 x 109 /L or <2 fold increase in plt from baseline or bleeding. Loss of response (LR) plt < 30 x 109/L or bleeding, from CR or R previously. Results: Of the 73 pts evaluated, 23(32%) were males and 50 (68%) females. The median age was 29 (range 3 to 75years), of which 13 (18%) were pediatric pts (age <12 yrs). 10 (14%) pts had no bleeding at presentation, 63 pts (86%) presented with bleeding, of which 23 pts (45%) had mild bleeding grade 1 -2, 27pts (37%) had moderate bleeding grade 3, and 4 pts had severe bleeding grade 4 including 1 pt with intracerebral bleed. 39 (53%)pts received dexamethasone, and 34 (47%)pts received prednisolone. 68 out of 73 pts (94%) had an initial response at 4 weeks, 54pts (74%) attained CR, and 14(20%) had R. 5pts had NR in whom steroids were discontinued and second-line therapy was started. Sustained response was assessed at 3 months in 58 out of 73pts, 15 were lost to follow-up. An overall sustained response CR and R was seen in 39 pts (67%), 15 (26%) had loss of response LR and 4 (7%) had no response NR. The results are summarised in table 1. 57 (88%) out of 73pts had treatment-related adverse events (TRAE) and 16 (22%) had no TRAE. The TRAE observed in our study include weight gain, infections, acne, fatigue, hyperglycemia, hypertension, dyspepsia, and others (insomnia, proximal myopathy, & central serous retinopathy-CSR). 1pt had proximal myopathy and 1 pt developed CSR. The severity of TRAE was graded as per CTCAE. There was no grade 4 or 5 TRAE. All TRAE resolved spontaneously or with treatment. TRAE is summarised in table 2. No significant difference was noticed between the prednisolone or the dexamethasone group either in terms of treatment outcomes or treatment-related adverse events. Conclusion: Our study shows comparable results between prednisolone and dexamethasone groups in initial and sustained response rates to first-line therapy in newly diagnosed ITP patients but a high incidence 88% of treatment-related adverse events in both groups. A shorter duration of steroids and affordable newer modalities of therapy in ITP is required to improve the overall well-being of ITP patients with lower middle income in India. Disclosures: No relevant conflicts of interest to declare. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comparative effectiveness of real-time ultrasound-guided tracheostomy and anatomic landmark percutaneous dilatational tracheostomy: a retrospective cohort study.

The role of ultrasound during various airway procedures has been in the spotlight in recent years. This study reconsiders the potential role and effectiveness of ultrasound use during percutaneous dilatational tracheostomy in intensive care patient population. This study aims to assess the impact of real-time ultrasound (US) use on complication rates and procedural success in percutaneous dilational tracheostomy (PDT) opened with forceps dilatation technique using anatomical landmarks. In this study, 59 patients who had undergone PDT in the intensive care unit (ICU) were reached. Written-electronic files and intensive care follow-up forms of the patients were reviewed retrospectively. The patients were divided into two groups: 44 patients in Group G (anatomical landmark PDT) and 15 patients in Group U (real-time US PDT). Demographic data, duration of intubation and ICU stay, discharge status, procedural characteristics and postoperative complications of the patients were determined. A total of 59 patients were analyzed. The mean age of the patients was 74.9±11.7 years, the mean tracheostomy duration was 33.3±20 days, and the mean duration of ICU stay was 60±45 days. Complications occurred in 62.7% of all patients. Minor bleeding was present in five (8.5%), moderate bleeding in 13 (22%), and major bleeding in 11 (18.6%) patients. In addition, pneumothorax was observed in one patient, misplacement of the tracheostomy cannula and emphysema in one patient, and esophageal injury in three patients. A total of 50 (84.7%) patients died, and nine (15.3%) patients continued to be treated in the ICU. Bleeding, hypoxemia, hypercapnia, tracheostomy opening time duration, and the number of attempts for the successful procedure were significantly higher in Group G than Group U (p<0.05). A negative correlation was found between the groups regarding the duration of tracheostomy (p = 0.001) and tracheostomy opening technique (p = 0.001). The use of real-time ultrasound in percutaneous tracheostomies opened under elective conditions in the ICU reduces the complications of hypoxemia, hypercapnia and bleeding by dwindling the duration of the procedure and the number of attempts than the conventional technique.

Tranexamic Acid vs Adrenaline for Controlling Iatrogenic Bleeding During Flexible Bronchoscopy: A Double-Blind Randomized Controlled Trial

The most commonly used topical hemostatic agents during flexible bronchoscopy (FB) are cold saline and adrenaline. Data on use of other agents such as tranexamic acid (TXA) for this purpose are limited. Is TXA effective and safe in controlling iatrogenic bleeding during FB compared with adrenaline? We conducted a cluster-randomized, double-blind, single-center trial in a tertiary teaching hospital. Patients were randomized in weekly clusters to receive up to three applications of TXA (100mg, 2mL) or adrenaline (0.2mg, 2mL, 1:10000) after hemostasis failure after three applications of cold saline (4 ° C, 5mL). Crossover was allowed (for up to three further applications) before proceeding with other interventions. Bleeding severity was graded by the bronchoscopist using a visual analog scale (VAS; 1= very mild, 10= severe). A total of 2,033 FBs were performed and 130 patients were randomized successfully to adrenaline (n= 65) or TXA (n= 65), whereas 12 patients had to be excluded for protocol violations (two patients from the adrenaline arm and 10 patients from TXA arm). Bleeding was stopped in 83.1%of patients (54/65) in both groups (P= 1). The severity of bleeding and number of applications needed for bleeding control were similar in both groups (adrenaline: mean VAS score, 4.9 ± 1.3 [n= 1.8 ± 0.8]; TXA: mean VAS score, 5.3 ± 1.4 [n= 1.8 ± 0.8]). Both adrenaline and TXA were more successful in controlling moderate bleeding (86.7%and 88.7%, respectively) than severe bleeding (40%and 58.3%, respectively; P= .008 and P= .012, respectively) and required more applications for severe bleeding (3.0 ± 0 and 2.4 ± 0.5, respectively) than moderate bleeding (1.7 ± 0.8 and 1.7 ± 0.8, respectively) control (P= .006 and P= .002, respectively). We observed no drug-related adverse events in either group. We found no significant difference between adrenaline and TXA for controlling noncatastrophic iatrogenic endobronchial bleeding after cold saline failure, adding to the body of evidence that TXA can be used safely and effectively during FB. ClinicalTrials.gov; No.: NCT04771923; URL: www. gov.

Placental Abruption as a Complication of Preeclampsia that Causes Fetal Distress

Background&#x0D; Placental abruption is a common complication of preeclampsia. It is an obstetric emergency which occurs when the placenta partially or completely separates from the uterine wall. The diagnosis is usually made clinically or objectively. It is relatively rare but put a serious risk for both the fetus and the mother.&#x0D; Case presentation &#x0D; We reported a case of a 32-year-old multigravida patient at 35-36 weeks gestation presented with moderate vaginal bleeding and lower abdominal pain. Her obstetric history included one premature vaginal delivery. Her blood pressure started to rise in the second trimester of pregnancy. The examination revealed that her blood pressure was 190/120 mmHg, she had pitting edema on her extremities and tender uterine fundus. The fetal heart rate was bradycardia at 100 beats per minute. Placental abruption and fetal distress were diagnosed. An emergency cesarean section was performed. Intraoperatively, the uterus showed intramural bleeding and was livid, with the beginning of Couvelaire-uterus. The uterus was left in situ.&#x0D; Conclusion&#x0D; As a conclusion, placental abruption interrupts the vital function of the placentae which leads to fetal hypoxia and even fetal death. It is an obstetric emergency that requires immediate intervention to save the fetus and reduce the risk of complications in the mother.

Impact of BNP level in patients with heart failure on major bleeding events after percutaneous coronary intervention

Abstract Aims The Academic Research Consortium for High Bleeding Risk (ARC-HBR) presents a bleeding risk assessment in antithrombotic therapy for patients post percutaneous coronary intervention (PCI). In Japanese patients, heart failure (HF), peripheral vascular disease, and frailty are established as bleeding risk factors in addition to ARC-HBR. However, it is unknown whether left ventricular function or severity of HF is associated with HBR. The aim of this study was to investigate the association between the severity of HF measured by BNP and future bleeding events after PCI. Methods Clinical Deep Data Accumulation System (CLIDAS), a multicenter database with 7 tertiary medical hospitals in JAPAN, was developed to collect data directly for patient characteristics, medications, laboratory test, physiological test, cardiac catheterization and PCI treatment in electronic medical records using Standardized Structured Medical Information eXchange Extended Storage (SS-MIX). This retrospective analysis using CLIDAS database included 7160 patients who underwent PCI during April 2014 and March 2020 in the participating hospitals and also who have completed 3-year follow-up were divided into two groups: No HF (n=6645) and HF (n=515). HF patients were furthermore divided based on high BNP (≥100 pg/ml) group (n=384) and low BNP (&amp;lt;100 pg/ml) group (n=131). Primary outcome was defined as bleeding events according to the moderate and severe bleeding in the GUSTO classification. In addition, secondary endpoint was major adverse cardiovascular events (MACE) defined as a composite of cardiac death, myocardial infraction and stroke. Results Multivariable Cox regression adjusted for age, sex, BMI, acute coronary syndrome, hypertension, diabetes, dyslipidemia, chronic kidney disease, hemodialysis, previous PCI, previous coronary artery bypass grafting, prior myocardial infraction, prior stroke, prior atrial fibrillation, prior PVD, left main trunk disease, multivessel disease, and anticoagulants use showed that HF with high BNP was significantly associated with bleeding events (hazard ratio [HR], 1.66; 95% confidence interval [CI], 1.10–2.50), MACE (HR, 2.16; 95% CI, 1.60–2.90), and all-cause death (HR, 1.74; 95% CI, 1.30–2.33), but not HF with low BNP. Conclusions The CLIDAS real-world database revealed that HF with high BNP was associated with future bleeding events, suggesting that bleeding risk might be altered depending on severity of HF. Funding Acknowledgement Type of funding sources: None.

Characterization of microglia/macrophage phenotypes in the spinal cord following intervertebral disc herniation.

Dogs frequently suffer from traumatic spinal cord injury (SCI). Most cases of SCI have a favorable prognosis but 40–50% of dogs with paraplegia and absence of nociception do not regain ambulatory abilities, eventually leading to euthanasia. Microglia and infiltrating macrophages play a crucial role in inflammatory process after SCI. However, little is known about microglia/macrophage phenotypes representing a potential target for future therapeutic strategies. In the present study, the microglia/macrophage phenotype was characterized by immunohistochemistry in the morphologically unaltered canine spinal cord (10 control dogs) and during acute and subacute SCI (1–4 and 5–10 days post injury, 9 and 8 dogs, respectively) using antibodies directed against IBA1, MAC387, MHC-II, lysozyme, EGR2, myeloperoxidase, CD18, CD204 and lectin from Griffonia simplicifolia (BS-1). The expression of these markers was also analyzed in the spleen as reference for the phenotype of histiocytic cells. Histological lesions were absent in controls. In acute SCI, 4 dogs showed mild to moderate hemorrhages, 2 dogs bilateral gray matter necrosis and 6 dogs mild multifocal axonal swellings and myelin sheath dilation. One dog with acute SCI did not show histological alterations except for few dilated myelin sheaths. In subacute SCI, variable numbers of gitter cells, axonal changes and dilated myelin sheaths were present in all dogs and large areas of tissue necrosis in 2 dogs. Neuronal chromatolysis was found in 3 dogs with acute and subacute SCI, respectively. In control dogs, microglia/macrophage constitutively expressed IBA1 and rarely other markers. In acute SCI, a similar marker expression was found except for an increase in MAC387-positive cells in the spinal cord white matter due to an infiltration of few blood-borne macrophages. In subacute SCI, increased numbers of microglia/macrophages expressed CD18, CD204 and MHC-II in the gray matter SCI indicating enhanced antigen recognition, processing and presentation as well as cell migration and phagocytosis during this stage. Interestingly, only CD204-positive cells were upregulated in the white matter, which might be related to gray-white matter heterogeneity of microglia as previously described in humans. The present findings contribute to the understanding of the immunological processes during SCI in a large animal model for human SCI.

Alterations on magnetic resonance imaging of the neonatal brain: correlations with prenatal risk factors and transfontanellar ultrasound findings.

To describe the alterations seen on magnetic resonance imaging (MRI) of the brain in newborns, correlating those alterations with the transfontanellar ultrasound (TFUS) findings, and to describe the main risk factors identified. We evaluated the examinations of 51 patients who were submitted to brain MRI with a neonatal protocol during hospitalization. We evaluated the MRI findings and correlated them with previous TFUS findings, using the last TFUS performed in order to minimize the risk of bias. Data were obtained from medical records, and the images were reviewed by a radiologist specializing in neuroimaging. Of the 51 patients evaluated, 21 (41.2%) were extremely preterm infants and 22 (43.1%) were extremely-low-birth-weight infants. Alterations were seen on 16 (31.4%) of the TFUS examinations and on 30 (58.8%) of the brain MRI scans, the most common finding being germinal matrix hemorrhage. The positive and negative predictive values of TFUS in relation to MRI were 87% and 54%, respectively. Because TFUS proved to be capable of distinguishing mild and moderate (grade I and II) germinal matrix hemorrhage from the severe forms (grades III and IV), it can be considered a good tool for screening and follow-up, especially in infants with severe disease and risk factors.

Feasibility of transbronchial lung cryobiopsy in patients with veno-venous extracorporeal membrane oxygenation support.

Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is essential life support in patients with severe acute hypoxaemic respiratory failure. However, biopsies should be considered for some patients with unknown aetiology. This study aims to evaluate the feasibility of transbronchial lung cryobiopsy (TBLC) in such patients. All patients with acute hypoxaemic respiratory failure of unknown aetiology who underwent TBLC with VV-ECMO support were retrospectively reviewed. Patients' characteristics, ventilation settings, procedure parameters, complications, pathological diagnosis and survival were summarised and analysed. Eight female and five male patients with VV-ECMO support underwent TBLC. The median age was 58 (interquartile range (IQR) 38-67) years old. Concurrent diseases were present in 10 of the 13 patients, seven of which were immunosuppressed. The median time between biopsy and VV-ECMO establishment was 2.0 (IQR 0.5-6.5) days. No patient died from the procedure. Neither pneumothorax nor severe bleeding occurred in any of the patients. Five of the 13 patients experienced moderate bleeding, and all bleeding events were successfully controlled with prophylactic balloon blockers. Pathological diagnosis by TBLC was obtained in all patients, and the diagnosis of diffuse alveolar damage was made in nine of them. In patients with VV-ECMO support, the TBLC procedure is generally safe when standardised bleeding prophylaxis is in place. TBLC contributes to identifying underlying aetiologies in patients with acute hypoxaemic respiratory failure of unknown aetiology.

Thin bronchoscopic cryobiopsy using a nasobronchial tube

BackgroundTransbronchial lung cryobiopsy is useful when diagnosing lung lesions. However, prevention of associated bleeding complications is essential. This study aimed to evaluate the safety and efficacy of our novel bronchoscopic cryobiopsy technique, which uses a long nasobronchial tube to prevent blood flooding the central airway.MethodsPatients with localized or diffuse lung lesions were prospectively enrolled and underwent cryobiopsy using a 1.9 mm diameter cryoprobe and a 4.0 mm diameter thin bronchoscope under conscious sedation. For cryobiopsy, a long silicone tube (inner diameter, 5.0 mm) was advanced through the nose to the target bronchus, then wedged to drain blood under thin-tube bronchoscopic control. The primary endpoint was the frequency of bleeding complications.ResultsOf the 80 patients initially enrolled, 73 that underwent at least one cryobiopsy were ultimately included. Mild bleeding during cryobiopsy occurred in 58 patients (79.5%), but there was no moderate or severe bleeding. Other complications occurred in four patients (two pneumothorax, one pneumomediastinum, and one pneumonia). Tube dislocation was noted in eight patients (11%). Cryobiopsy specimens were significantly larger than forceps biopsy specimens (9.0 mm2 vs. 2.7 mm2, P < .001) and allowed specific diagnoses in 50 patients (68.5%).ConclusionsThin bronchoscopic cryobiopsy using a nasobronchial tube in consciously sedated patients is safe and effective.Trial registration Date of registration: 24/06/2019. UMIN-Clinical Trials Registry; Identifier: UMIN000037156 https://www.umin.ac.jp/ctr/index.htm

Protocolized management of bleeding in hospitals in The Netherlands in patients treated with direct oral anticoagulants

Objective To investigate and describe the protocolized treatment of DOAC-related bleeds in all Dutch hospitals. Methods From August to December 2020 a nationwide survey among all 70 hospitals in the Netherlands was conducted on their protocols for management of bleeding in patients treated with direct oral anticoagulants (DOACs, i.e. apixaban, edoxaban, rivaroxaban and dabigatran). The protocols were assessed the following characteristics: bleeding definitions (mild, moderate and severe bleed), diagnostic parameters (hemoglobin [Hb], loss of blood, surgical procedure needed, etc), first and second choice of treatment, effectiveness criteria and the level of evidence/references upon which protocols were based. Results All 70 hospitals responded (100%). We received 69 protocols in total, 6 of which were identical because hospitals worked together. In 35 (50%) of the protocols a definition of minor, moderate or severe bleeds was described. Diagnostic parameters for bleeds were present in 2%, 41% and 47% of protocols for a mild, moderate and severe bleed. While the first choice treatment for severe bleeding under dabigatran was idarucizumab in 96% of protocols, considerably more therapeutic options (mostly different prothrombin complex concentrate (PCC) doses) are described for Xa inhibitors. When considering criteria for effectiveness more than 90% of protocols did not have a clear description. Conclusion This study provides an overview of the current state of protocols for management of DOAC-related bleeding in The Netherlands. Protocols vary in the content of information provided and often do not include information, especially for diagnostic criteria and criteria for establishing the effectiveness of the intervention. The results of this study can assist in improving and harmonizing the protocols.

A simple and reliable adult uncuffed endotracheal tube for combined forceps and cryoprobe biopsy during bronchoscopy.

IntroductionCombined forceps and cryoprobe biopsy during bronchoscopy are increasingly used. However, the adult standard cuffed endotracheal tube (SCETT) is can be limited by general anaesthesia and neuromuscular blockade. An adult uncuffed endotracheal tube (UCETT) might provide simple and safe airway support in stable patients during forceps and cryoprobe biopsy under spontaneous respiration.MethodsA retrospective review of stable patients undergoing forceps and cryoprobe biopsy was performed. They were divided into a UCETT group (N = 33) and a SCETT group (N = 27). The primary technical outcome was the successful intubation and completion of bronchoscopy. The primary safety outcome was the incidence of desaturation events. Recovery time and side effects were also recorded.ResultsUCETTs and SCETTs were successfully inserted, and bronchoscopic procedures were completed in all patients. Only 3/33 (9.1%) patients in the UCETT group exhibited a drop of SPO2 < 90% during the bronchoscopy, compared to 2/27 (7.4%) patients in the SCETT group (P = 0.545). Patients recovered faster in the UCETT group than those in the SCETT group. Major bleeding, laryngospasm and major arrhythmias did not occur in either group. Incidences of sinus tachycardia, incidences of vomiting, minor and moderate bleeding and premature atrial contractions were not significantly different between the two groups. Nausea occurred in 5/33 (15.2%) patients in the UCETT group, compared to 11/27 (40.7%) in the SCETT group.ConclusionThis study suggests that UCETT under spontaneous respiration can provide satisfactory airway support and a shorter recovery time in stable patients; thus, it may be an option to assist forceps and cryoprobe biopsy.

Effect of Chronic Antiplatelet and Anticoagulant Medication in Neck Hematoma and Perioperative Outcomes after Carotid Endarterectomy

A retrospective analysis of neck hematoma, stroke, and mortality after symptomatic and asymptomatic carotid endarterectomy (CEA) was conducted, to determine the most appropriate perioperative medication for these patients. Thirty-day outcomes of moderate and severe neck bleeding were also investigated. Patients undergoing CEA in a Vascular Surgery department were analyzed (2015-2019). Preprocedure antithrombotic medication (from the 5 days prior to surgery) was identified. End point predictors were identified by univariate and multivariable analyses and adjusted for confounders. A total of 304 CEA were included. Almost half of the included patients (49.67%) were under low-dose aspirin, 17.55% other single antiplatelet agent, 12.59% dual antiplatelet therapy, 8.61% anticoagulation, and 10.92% no antithrombotic therapy. There was a 8.22% rate of important hematoma, including 4.93% severe (requiring surgical exploration) hematomas and a 30-day all-stroke incidence of 2.94% in symptomatic and 1.79% asymptomatic patients (P=0.51). When compared to aspirin, severe hematoma was more prevalent with single clopidogrel or triflusal (relative risk [RR] 4.25, P=0.11), dual antiplatelet group (RR 11.84, P=0.002), and anticoagulation (RR 8.604, P=0.02). Dual antiaggregation and anticoagulation did not confer postoperative stroke protection compared to single aspirin in either symptomatic or asymptomatic patients. Nonsignificant higher intrahospital mortality was noted in no medication, dual antiplatelet, and anticoagulation groups in contrast to aspirin. Severe neck bleeding was associated with increased congestive heart failure (9.26-fold, P=0.03) and longer hospital stay (11.20±24.69days vs. 3.18±4.79 with no bleeding, P<0.001), with a tendency for higher hospital readmission at 30 days (4.66-fold, P=0.13). Mortality and stroke rates were similar. Double antiaggregation and anticoagulation did not confer better perioperative outcomes after elective CEA in our study. These regimens were associated with an increased risk of neck hematoma, especially severe bleeding, with similar rates of neurologic events in both symptomatic and asymptomatic patients and no mortality benefit. Monotherapy with aspirin appears to be the safest perioperative antithrombotic regimen for elective CEA.

Plasma transfusion practices: A multicentre electronic audit.

Plasma is often transfused to patients with bleeding or requiring invasive procedures and with abnormal tests of coagulation. Chart audits find half of plasma transfusions unnecessary, resulting in avoidable complications and costs. This multicentre electronic audit was conducted to determine the proportion of plasma transfused without an indication and/or at a sub-therapeutic dose. Data were extracted on adult inpatients in 2017 at five academic sites from the hospital electronic chart, laboratory information systems and the Canadian Institute for Health Information Discharge Abstract Database. Electronic criteria for plasma transfusion outside recommended indications were: (1) international normalized ratio (INR) < 1.5 with no to moderate bleeding; (2) INR ≥ 1.5, with no to mild bleeding and no planned procedures; and (3) no INR before or after plasma infusion. Sub-therapeutic dose was defined as ≤2units transfused. In 1 year, 2590 patients received 6088 plasma transfusions encompassing 11,490 units of plasma occurred at the five sites. 77.7% of events were either outside indications or under-dosed. Of these, 34.8% of plasma orders had no indication identified, and 62% of these occurred in non-bleeding patients and no planned procedure with an isolated elevated INR. 70.7% of transfusions were under-dosed. Most plasma transfusions occurred in the intensive care unit or the operating room. Inter-hospital variability in peri-transfusion testing and dosing was observed. The majority of plasma transfusions are sub-optimal. Local hospital culture may be an important driver. Electronic audits, with definitions employed in this study, may be a practical alternative to costly chart audits.

Can the ShangRing bring us closer to endorsing early infant male circumcision in sub-Saharan Africa?

Can the ShangRing bring us closer to endorsing early infant male circumcision in sub-Saharan Africa?