Rationale for the Potential Use of Recombinant Activated Factor VII in Severe Post-Partum Hemorrhage.

Severe post-partum hemorrhage (PPH) is a major cause of maternal mortality worldwide. Recombinant activated factor VII (rFVIIa) has recently been approved by the European Medicines Agency for the treatment of severe PPH if uterotonics fail to achieve hemostasis. Although large randomized controlled trials are lacking, accumulated evidence from smaller studies and international registries supports the efficacy of rFVIIa alongside extended standard treatment to control severe PPH. Because rFVIIa neither substitutes the activity of a missing coagulation factor nor bypasses a coagulation defect in this population, it is not immediately evident how it exerts its beneficial effect. Here, we discuss possible mechanistic explanations for the efficacy of rFVIIa and the published evidence in patients with severe PPH. Recombinant FVIIa may not primarily increase systemic thrombin generation, but may promote local thrombin generation through binding to activated platelets at the site of vascular wall injury. This explanation may also address safety concerns that have been raised over the administration of a procoagulant molecule in a background of increased thromboembolic risk due to both pregnancy-related hemostatic changes and the hemorrhagic state. However, the available safety data for this and other indications are reassuring and the rates of thromboembolic events do not appear to be increased in women with severe PPH treated with rFVIIa. We recommend that the administration of rFVIIa be considered before dilutional coagulopathy develops and used to support the current standard treatment in certain patients with severe PPH.

Clinical guideline on reversal of direct oral anticoagulants in patients with life threatening bleeding.

BACKGROUND: Anticoagulation is essential for the treatment and prevention of thromboembolic events. Current guidelines recommend direct oral anticoagulants (DOACs) over vitamin K antagonists in DOAC-eligible patients. The major complication of anticoagulation is serious or life-threatening haemorrhage, which may necessitate prompt haemostatic intervention. Reversal of DOACs may also be required for patients in need of urgent invasive procedures. This guideline from the European Society of Anaesthesiology and Intensive Care (ESAIC) aims to provide evidence-based recommendations and suggestions on how to manage patients on DOACs undergoing urgent or emergency procedures including the treatment of DOAC-induced bleeding. DESIGN: A systematic literature search was performed, examining four drug comparators (dabigatran, rivaroxaban, apixaban, edoxaban) and clinical scenarios ranging from planned to emergency surgery with the outcomes of mortality, haematoma growth and thromboembolic complications. The GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methodology was used to assess the methodological quality of the included studies. Consensus on the wording of the recommendations was achieved by a Delphi process. RESULTS: So far, no results from prospective randomised trials comparing two active comparators (e.g. a direct reversal agent and an unspecific haemostatic agent such as prothrombin complex concentrate: PCC) have been published yet and the majority of publications were uncontrolled and observational studies. Thus, the certainty of evidence was assessed to be either low or very low (GRADE C). Thirty-five recommendations and clinical practice statements were developed. During the Delphi process, strong consensus (>90% agreement) was achieved in 97.1% of recommendations and consensus (75 to 90% agreement) in 2.9%. DISCUSSION: DOAC-specific coagulation monitoring may help in patients at risk for elevated DOAC levels, whereas global coagulation tests are not recommended to exclude clinically relevant DOAC levels. In urgent clinical situations, haemostatic treatment using either the direct reversal or nonspecific haemostatic agents should be started without waiting for DOAC level monitoring. DOAC levels above 50 ng ml-1 may be considered clinically relevant necessitating haemostatic treatment before urgent or emergency procedures. Before cardiac surgery under activated factor Xa (FXa) inhibitors, the use of andexanet alfa is not recommended because of inhibition of unfractionated heparin, which is needed for extracorporeal circulation. In the situation of DOAC overdose without bleeding, no haemostatic intervention is suggested, instead measures to eliminate the DOACs should be taken. Due to the lack of published results from comparative prospective, randomised studies, the superiority of reversal treatment strategy vs. a nonspecific haemostatic treatment is unclear for most urgent and emergency procedures and bleeding. Due to the paucity of clinical data, no recommendations for the use of recombinant activated factor VII as a nonspecific haemostatic agent can be given. CONCLUSION: In the clinical scenarios of DOAC intake before urgent procedures and DOAC-induced bleeding, practitioners should evaluate the risk of bleeding of the procedure and the severity of the DOAC-induced bleeding before initiating treatment. Optimal reversal strategy remains to be determined in future trials for most clinical settings.

Allogeneic Blood Transfusion and Risk of Postoperative Complications in Patients with Mild and Moderate Anemia of Any Cause? A Retrospective Cohort Study in Total Revision Hip Surgery.

Introduction: Patients undergoing revision total hip surgery (RTHS) have a high prevalence of mild and moderate preoperative anemia, associated with adverse outcomes. The aim of this study was to investigate the association of perioperative allogeneic blood transfusions (ABT) and postoperative complications in preoperatively mild compared to moderate anemic patients undergoing RTHS who did not receive a diagnostic anemia workup and treatment before surgery. Methods: We included 1,765 patients between 2007 and 2019 at a university hospital. Patients were categorized according to their severity of anemia using the WHO criteria of mild, moderate, and severe anemia in the first Hb level of the case. Patients were grouped as having received no ABT, 1-2 units of ABT, or more than 2 units of ABT. Need for intraoperative ABT was assessed in accordance with institutional standards. Primary endpoint was the compound incidence of postoperative complications. Secondary outcomes included major/minor complications and length of hospital and ICU stay. Results: Of the 1,765 patients, 31.0% were anemic of any cause before surgery. Transfusion rates were 81% in anemic patients and 41.2% in nonanemic patients. The adjusted risks for compound postoperative complication were significantly higher in patients with moderate anemia (OR 4.88, 95% CI: 1.54-13.15, p = 0.003) but not for patients with mild anemia (OR 1.93, 95% CI: 0.85-3.94, p < 0.090). Perioperative ABT was associated with significantly higher risks for complications in nonanemic patients and showed an increased risk for complications in all anemic patients. In RTHS, perioperative ABT as a treatment for moderate preoperative anemia of any cause was associated with a negative compound effect on postoperative complications, compared to anemia or ABT alone. Discussion: ABT is associated with adverse outcomes of patients with moderate preoperative anemia before RTHS. For this reason, medical treatment of moderate preoperative anemia may be considered.

Clinical Course and Management of Patients with Emergency Surgery Treated with Direct Oral Anticoagulants or Vitamin K Antagonists-Results of the German Prospective RADOA-Registry.

(1) Background: The clinical management of anticoagulated patients treated with direct oral anticoagulants (DOAC) or Vitamin K antagonists (VKA) needing emergency surgery is challenging. (2) Methods: The prospective German RADOA registry investigated treatment strategies in DOAC- or VKA-treated patients needing emergency surgery within 24 h after admission. Effectiveness was analysed by clinical endpoints including major bleeding. Primary observation endpoint was in hospital mortality until 30 days after admission. (3) Results: A total of 78 patients were included (DOAC: 44; VKA: 34). Median age was 76 years. Overall, 43% of the DOAC patients and 79% of the VKA patients were treated with prothrombin complex concentrates (PCC) (p = 0.002). Out of the DOAC patients, 30% received no hemostatic treatment compared to 3% (1/34) of the VKA patients (p = 0.002), and 7% of the DOAC patients and 21% of the VKA patients developed major or clinically relevant non-major bleeding at the surgical site (p = 0.093). In-hospital mortality was 13% with no significant difference between the two treatment groups (DOAC: 11%, VKA: 15%; p > 0.20). (4) Conclusions: The 30-day in-hospital mortality rate was comparable between both patient groups. VKA patients required significantly more hemostatic agents than DOAC patients in the peri- and postoperative surgery period.

Peripartum Haemorrhage: Haemostatic Aspects of the Updated Peripartum Haemorrhage Guideline of the German-Speaking Countries.

Background: Peripartum haemorrhage (PPH) is a potentially life-threatening complication. Although still rare, the incidence of peripartal haemorrhage is rising in industrialised countries and refractory bleeding remains among the leading causes of death in the peripartal period. Summary: The interdisciplinary German, Austrian, and Swiss guideline on "Peripartum Haemorrhage: Diagnostics and Therapies" has reviewed the evidence for the diagnostics and medical, angiographic, haemostatic, and surgical treatment and published an update in September 2022 . This article reviews the updated recommendations regarding the early diagnosis and haemostatic treatment of PPH. Keystones of the guideline recommendations are the early diagnosis of the bleeding by measuring blood loss using calibrated collector bags, the development of a multidisciplinary treatment algorithm adapted to the severity of bleeding, and the given infrastructural conditions of each obstetric unit, the early and escalating use of uterotonics, the therapeutic, instead of preventative, use of tranexamic acid, the early diagnostics of progressive deficiencies of coagulation factors or platelets to facilitate a tailored and guided haemostatic treatment with coagulation factors, platelets as well as packed red blood cells and fresh frozen plasma when a massive transfusion is required. Key Messages: Essential for the effective and safe treatment of PPH is the timely diagnosis. The diagnosis of PPH requires the measurement rather than estimation of blood loss. Successful treatment of PPH consists of a multidisciplinary approach involving surgical and haemostatic treatments to stop the bleeding. Haemostatic treatment of PPH starts early after diagnosis and combines tranexamic acid, an initially ratio-driven transfusion with RBC:plasma:PC = 4:4:1 (when using pooled or apheresis PC) and finally a goal-directed substitution with coagulation factor concentrates for proven deficiencies. Early monitoring of coagulation either by standard parameters or viscoelastic methods facilitates goal-directed haemostatic treatment.

Management of edoxaban therapy and clinical outcomes in patients undergoing major or nonmajor surgery: a subanalysis of the EMIT-AF/VTE study.

BACKGROUND: Optimising periprocedural management of direct oral anticoagulation in patients with atrial fibrillation on chronic treatment undergoing major surgeries is an important aspect of balancing the risk of surgery-related bleeding with the risk of thromboembolic events, which may vary by surgery type. METHODS: This subanalysis of the prospective EMIT-AF/VTE programme assessed periprocedural-edoxaban management, according to physicians' decisions, and bleeding and thromboembolic event rates in patients who underwent major vs. nonmajor surgeries. Edoxaban interruption and clinical outcomes were compared between major vs. nonmajor surgeries and between renal function subgroups (creatinine clearance [CrCL] ≤ 50 mL/min vs. > 50 mL/min). RESULTS: We included 276 major and 512 nonmajor surgeries. The median pre- and postprocedural duration of edoxaban interruption in major vs. nonmajor surgeries was 4 vs. 1 days, whereas median duration of interruption for those with preprocedural-only and postprocedural-only interruption was 2 vs. 1 days and 2 vs. 0 days, respectively (P < 0.0001). Rates of all bleeding and clinically relevant nonmajor bleeding were numerically higher in major vs. nonmajor surgeries. Event rates (number of events per 100 surgeries) were low overall (< 6 events per 100 surgeries), independent of renal function subgroups. CONCLUSION: In this subanalysis of the EMIT-AF/VTE programme, periprocedural-edoxaban interruption was significantly longer in patients undergoing major vs. nonmajor surgery. This clinician-driven approach was associated with low rates of bleeding and thromboembolic events following both major and nonmajor surgeries. TRIAL REGISTRATION: NCT02950168, registered October 31, 2016; NCT02951039, registered November 1, 2016.

Predictive Factors and Clinical Events Associated with Edoxaban Interruption and Heparin Bridging Strategy: EMIT-AF/VTE.

Patients treated with edoxaban may require diagnostic and therapeutic procedures that involve edoxaban interruption. Although heparin bridging strategies are not recommended, heparin is frequently used in clinical practice. However, whether heparin use decreases thromboembolic risk remains unclear, and the potential for increased periprocedural bleeding remains a concern. Here, we report factors predicting edoxaban interruption and the use of heparin bridging strategies and associated clinical events from Global EMIT-AF/VTE, a multicenter, prospective, noninterventional study (Clinicaltrials.gov NCT02950168). Eligible patients are adults with atrial fibrillation or venous thromboembolism treated with edoxaban who underwent a diagnostic or therapeutic procedure. Edoxaban interruption, heparin bridging strategies, and clinical event data were collected from 5 days before procedure through 29 days afterwards. Edoxaban was interrupted in 1222/2089 procedures (58.5%); a heparin bridging strategy was used during 178 (14.6%) of these interruptions. Patients who received periprocedural heparin had higher baseline HAS-BLED (2.4±1.0 vs 1.9±1.1, P <0.0001) scores and similar CHA2DS2-VASc (3.6±1.6 vs 3.4±1.6, P = 0.09) scores versus patients who did not. HAS-BLED score >3 and high EHRA procedural risk predicted both edoxaban interruption and the use of a heparin bridging strategy, whereas CHA2DS2-VASc scores did not predict either. Bleeding and ischemic event rates were low; the all-bleeding rate was higher with the use of a heparin bridging strategy versus without (6.2% vs 3.1%, P = 0.04). Periprocedural heparin use was associated with higher bleeding rates, but not with lower thromboembolic risk. Individual patient and procedural bleeding risks appear to contribute more than stroke risk to clinicians' consideration of a heparin bridging strategy.

Edoxaban use in the context of dental procedures: analysis from the EMIT-AF/VTE database.

INTRODUCTION: Literature reviews support continuing anticoagulation during dental procedures. However, studies often present grouped anticoagulation data, and information on individual anticoagulant management would be helpful to dentists. The Edoxaban Management in Diagnostic and Therapeutic Procedures (EMIT-AF/VTE) programme (NCT02950168; NCT02951039) demonstrated low periprocedural bleeding and thrombotic event rates in patients with atrial fibrillation receiving edoxaban. AIMS: To report periprocedural edoxaban interruption and clinical events in patients from EMIT-AF/VTE who underwent dental procedures. METHODS: Dental procedures were categorised by type (cleaning/noncleaning). Edoxaban interruption, bleeding events, and thrombotic events were observed 5 days preprocedure through 29 days postprocedure. RESULTS: Overall, 196 patients underwent 350 cleaning and/or noncleaning procedures; most patients (171/196 [87.2%]) underwent noncleaning procedures (282/350 [80.6%]), whereas 48/196 (24.5%) underwent 68/350 (19.4%) cleaning procedures. Edoxaban was uninterrupted for most cleanings (53/68 [77.9%]). Preprocedural interruption was common for single and multiple tooth extractions (single, 67/100 [67.0%]; multiple, 16/30 [53.3%]). The only major bleeding occurred after an unrelated cleaning. Minor bleeding occurred in 1/68 (1.5%) cleaning and 4/282 (1.4%) noncleaning procedures. There were no thrombotic events. CONCLUSIONS: For most cleanings, edoxaban was not interrupted, whereas preprocedural interruption was more common for tooth extractions. Overall, bleeding rates were low, and no thrombotic events occurred.

Die perioperative Gabe von Tranexamsäure. / The Perioperative Application of Tranexamic Acid.

The application of tranexamic acid (TXA) during endoprosthetic surgical procedures has significantly increased in recent years. Due its ability to reduce perioperative blood loss and avert the need for blood transfusions as well as wound drainage, TXA is becoming part of a 'standard practice'. However, TXA is currently not approved for the application during endoprosthetic procedures and therefore, a benefit-risk analysis should always be conducted. Prophylactic administration of TXA without prior patient consent is only justified if fibrinolytic bleeding is expected and there are no contraindications or relevant risk factors for thromboembolic complications. Respectively, no patient consent is required when a therapeutic dose of TXA is administered in the context of fibrinolytic bleeding. The following guidelines provide updated recommendations based on the current state of knowledge on TXA optimal timing, routes of administration and dosing regimen.

Indications for the Use of Therapeutic Plasma in Adult Patients.

Background: Different preparations for therapeutic plasma are available on the market. The German hemotherapy guideline has been completely updated in 2020 and, for this purpose, has reviewed the evidence for the most frequent clinical indications for the use of therapeutic plasma in adult patients. Summary: The German hemotherapy guideline has reviewed the evidence for the following indications for the use of therapeutic plasma in the adult patient: massive transfusion and bleeding, severe chronic liver disease, disseminated intravascular coagulation, plasma exchange for TTP, and the rare hereditary FV and FXI deficiencies. The updated recommendations for each indication are discussed on the background of existing guidelines and new evidence. For most indications, the quality of evidence is low due to missing prospective randomized trials or rare diseases. However, due to the "balanced" content of coagulation factors and inhibitors therapeutic plasma remains an important pharmacological treatment option in clinical situations with an already activated coagulation system. Unfortunately, the "physiological" content of coagulation factors and inhibitors limits the efficacy in clinical scenarios with high blood losses. Key Messages: The evidence for the use of therapeutic plasma for the replacement of coagulation factors due to massive bleeding is poor. Coagulation factor concentrates seem to be more appropriate for this indication, although the quality of evidence is also low. However, for diseases with an activated coagulation or endothelial system (e.g., disseminated intravascular coagulation, TTP) the balanced replacement of coagulation factors, inhibitors, and proteases may be of advantage.

[The costs of preoperative anemia in hip joint revision surgery]. / Die Kosten der präoperativen Anämie bei Hüftgelenkrevisionsoperationen.

BACKGROUND: Anemia is highly prevalent in patients before hip joint revision surgery (HJRS) and is associated with an increased complication rate. This paper is the first to investigate costs, real diagnosis-related group (DRG) revenues and case coverage of preoperative anemia in elective HJRS. METHODS: Medical data, transfusions, costs, and revenues of all patients undergoing HJRS at two campuses of the Charité -Universitätsmedizin Berlin between 2010 and 2017 were used for subgroup analyses and linear regressions. RESULTS: Of 1187 patients included 354 (29.8%) showed preoperative anemia. A total of 565 (47.6%) patients were transfused with a clear predominance of anemic patients (72.6% vs. 37.0%, p < 0.001). Costs (12,318€ [9027;20,044€] vs. 8948€ [7501;11,339€], p < 0.001) and revenues (11,788€ [8992;16,298€] vs. 9611€ [8332;10,719€], p < 0.001) were higher for preoperatively anemic patients and the coverage was deficient (-1170€ [-4467;1238€] vs. 591€ [-1441;2103€], p < 0.001). In anemic patients, case contribution margins decreased with increasing transfusion rates (p ≤ 0.001). Comorbidities had no significant economic impact. CONCLUSION: Preoperative anemia and perioperative transfusions in HJRS are associated with increased treatment costs and a financial undercoverage for healthcare providers and health insurance companies. Concepts for the treatment of preoperative anemia (e.g. patient blood management) could reduce treatment costs in the medium term.

Pleural effusions are associated with adverse outcomes after cardiac surgery: a propensity-matched analysis.

BACKGROUND: Pleural effusions commonly occur in patients recovering from cardiac surgery; however, the impact on outcomes is not well characterized. The purpose of this study is to characterize the clinical outcomes of cardiac surgery patients with pleural effusion. METHODS: All patients undergoing cardiac surgery between 2006 and 2019 at a tertiary care university hospital were included in this observational, cross-sectional analysis using propensity matching. RESULTS: Of 11,037 patients that underwent cardiac surgery during the study period, 6461 (58.5%) had no pleural effusion (Group 0), 3322 (30.1%) had pleural effusion only (Group 1), and 1254 (11.4%) required at least one secondary drainage procedure after the index operation (Group 2). After propensity matching, the mortality of patients who underwent secondary drainage procedures was 6.1% higher than in Group 1 (p < 0.001). Intensive care unit (ICU) stay was longer for those with pleural effusions (18 [IQR 9-32] days in Group 2, 10 [IQR 6-17] days for Group 1, and 7 [IQR 4-11] days for Group 0, p < 0.001). Patients with pleural effusions had a higher incidence of hemodialysis (246 [20.0%] in Group 2, 137 [11.1%] in Group 1, 98 [7.98%] in Group 0), and a longer ventilation time in the ICU (57 [IQR 21.0-224.0] hours in Group 2, 25.0 [IQR 14.0-58.0] hours in Group 1, 16.0 [IQR 10.0-29.0] hours in Group 0). CONCLUSION: Pleural effusions, especially those that require a secondary drainage procedure during recovery, are associated with significantly worse outcomes including increased mortality, longer length of stay, and higher complication rates. These insights may be of great interest to scientists, clinicians, and industry leaders alike to foster research into innovative methods for preventing and treating pleural effusions with the aim of improving outcomes for patients recovering from cardiac surgery.

Pharmacokinetics of Phenprocoumon in Emergency Situations-Results of the Prospective Observational RADOA-Registry (Reversal Agent Use in Patients Treated with Direct Oral Anticoagulants or Vitamin K Antagonists Registry).

Background: Phenprocoumon has been used as an oral anticoagulant in patients with thromboembolic disease for more than 40 years. So far its pharmacokinetics have not been analyzed in emergency situations. Methods: Phenprocoumon-treated patients with major bleeding or urgent surgery were included in a prospective, observational registry. Phenprocoumon drug concentrations were analyzed in samples, collected as part of routine care using ultraperformance liquid chromatography tandem mass spectrometry. Moreover, anticoagulant intensity and drug half-life (t1/2) were calculated. Results: 115 patients were included. Phenprocoumon levels declined over time with a half-life of 5.27 and 5.29 days in patients with major bleedings (n = 82) and with urgent surgery (n = 33). Baseline phenprocoumon levels were 2.2 times higher in the bleeding group compared to the surgery group (1.92 vs. 0.87 ng/mL, p < 0.0001). International normalized ratio (INR) values decreased rapidly during the first 24 h. In 27.6% of patients a rebound of INR (recurrent increase > 1.5) was observed which was associated with significantly increased bleeding rates (22% vs. 4.2% in patients with or without INR rebound, p = 0.012). Conclusions: In emergency situations, the long half-life of phenprocoumon may cause INR rebound and associated recurrent bleedings. Optimal management may need to include repeated vitamin K supplementation over days.

Factors associated with failed epidural blood patch after accidental dural puncture in obstetrics: a prospective, multicentre, international cohort study.

BACKGROUND: Epidural blood patch is commonly used for management of post-dural puncture headache after accidental dural puncture. The primary aim was to determine factors associated with failed epidural blood patch. METHODS: In this prospective, multicentre, international cohort study, parturients ≥18 yr receiving an epidural blood patch for treatment of post-dural puncture headache were included. Failed epidural blood patch was defined as headache intensity numeric rating scale (NRS) score ≥7 in the upright position at 4, 24, or 48 h, or the need for a second epidural blood patch, and complete success by NRS=0 at 0-48 h after epidural blood patch. All others were considered partial success. Multinominal logistic regression was used for statistical analyses with P<0.01 considered statistically significant. RESULTS: In all, 643 women received an epidural blood patch. Complete data to classify failure were available in 591 (91.9%) women. Failed epidural blood patch occurred in 167 (28.3%) patients; 195 (33.0%) were completely successful and 229 (38.7%) partially successful. A total of 126 women (19.8%) received a second epidural blood patch. A statistically significant association with failure was observed in patients with a history of migraine, when the accidental dural puncture occurred between lumbar levels L1/L3 compared with L3/L5 and when epidural blood patch was performed <48 h compared with ≥48 h after accidental dural puncture. In patients having radiological investigations, three intracranial bleeds were diagnosed. CONCLUSIONS: Failed epidural blood patch occurred in 28.3% of women. Independent modifiable factors associated with failure were higher lumbar level of accidental dural puncture and short interval between accidental dural puncture and epidural blood patch. A history of migraine was associated with a higher risk of second epidural blood patch. CLINICAL TRIAL REGISTRATION: NCT02362828.

Outcome of necrotizing fasciitis and Fournier's gangrene with and without hyperbaric oxygen therapy: a retrospective analysis over 10 years.

BACKGROUND: Necrotizing soft tissue infections (NSTI) require immediate radical debridement, broad-spectrum antibiotics and intensive care. Hyperbaric oxygen therapy (HBOT) may be performed adjunctively, but unequivocal evidence for its benefits is still lacking. METHODS: We performed a retrospective single-center study including 192 patients with necrotizing fasciitis or Fournier's gangrene to assess in-hospital mortality and outcome dependent on patient, disease and treatment characteristics with or without HBOT. RESULTS: The in-hospital mortality rate was 27.6%. Factors associated with increased mortality according to multivariate analysis were higher age, affection of multiple or problem localizations (odds ratio (OR) = 2.88, P = 0.003), ineligibility for HBOT despite clinical indication (OR = 8.59, P = 0.005), pathogens in blood cultures (OR = 3.36, P = 0.002), complications (OR = 10.35, P < 0.001) and sepsis/organ dysfunction (OR = 19.58, P < 0.001). Factors associated with better survival included vacuum-assisted wound closure (OR = 0.17, P < 0.001), larger number of debridements (OR = 0.83, P < 0.001) and defect closure with mesh graft (OR = 0.06, P < 0.001) or flap (OR = 0.09, P = 0.024). When participants were stratified into subgroups without requirement of HBOT (n = 98), treated with HBOT (n = 83) and ineligible for HBOT due to contraindications (n = 11), the first two groups had similar survival rates (75.5% vs. 73.5%) and comparable outcome, although patients with HBOT suffered from more severe NSTI, reflected by more frequent affection of multiple localizations (P < 0.001), sepsis at admission (P < 0.001) and intensive care treatment (P < 0.001), more debridements (P < 0.001) and a larger number of antibiotics (P = 0.001). In the subgroup ineligible for HBOT, survival was significantly worse (36.4%, P = 0.022). CONCLUSION: These results point to a benefit from HBOT for treatment of NSTI in critically ill patients.

Thromboprophylaxis with argatroban in critically ill patients with sepsis: a review.

During sepsis, an initial prothrombotic shift takes place, in which coagulatory acute-phase proteins are increased, while anticoagulatory factors and platelet count decrease. Further on, the fibrinolytic system becomes impaired, which contributes to disease severity. At a later stage in sepsis, coagulation factors may become depleted, and sepsis patients may shift into a hypo-coagulable state with an increased bleeding risk. During the pro-coagulatory shift, critically ill patients have an increased thrombosis risk that ranges from developing micro-thromboses that impair organ function to life-threatening thromboembolic events. Here, thrombin plays a key role in coagulation as well as in inflammation. For thromboprophylaxis, low molecular weight heparins (LMWH) and unfractionated heparins (UFHs) are recommended. Nevertheless, there are conditions such as heparin resistance or heparin-induced thrombocytopenia (HIT), wherein heparin becomes ineffective or even puts the patient at an increased prothrombotic risk. In these cases, argatroban, a direct thrombin inhibitor (DTI), might be a potential alternative anticoagulatory strategy. Yet, caution is advised with regard to dosing of argatroban especially in sepsis. Therefore, the starting dose of argatroban is recommended to be low and should be titrated to the targeted anticoagulation level and be closely monitored in the further course of treatment. The authors of this review recommend using DTIs such as argatroban as an alternative anticoagulant in critically ill patients suffering from sepsis or COVID-19 with suspected or confirmed HIT, HIT-like conditions, impaired fibrinolysis, in patients on extracorporeal circuits and patients with heparin resistance, when closely monitored.

Intracranial bleeding under vitamin K antagonists or direct oral anticoagulants: results of the RADOA registry.

BACKGROUND AND PURPOSE: The use of direct oral anticoagulants (DOAC) has increased sharply and DOAC are the oral anticoagulant therapy (OAT) of choice for the majority of patients with newly-diagnosed atrial fibrillation. Intracranial hemorrhage is the most severe adverse event of OAT. Systematic data on the course of intracranial hemorrhage under DOAC compared to vitamin K antagonists (VKA) are warranted to enable shared decision making in AF patients needing OAT. METHODS: This is a secondary analysis of the patients with intracranial bleedings from the prospective multicenter emergency department-based RADOA registry, which collected data on patients admitted with major bleeding while taking VKA or DOAC. The primary endpoint was in-hospital mortality until day 30. We evaluated hematoma volume and short-term clinical outcomes in relation to the extent of active OAT according to coagulation parameters and OAT plasma levels measured by UPLC-MS/MS. RESULTS: Of 193 patients with major bleeding, 109 (56.5%) had intracranial hemorrhage [52.3% intracerebral (ICH), 33.9% subdural (SDH), 11.0% subarachnoidal (SAH)]. 64 (58.7%) were on VKA and 45 (41.2%) were on DOAC. On admission, we could confirm active anticoagulation in 97.7% of VKA-treated patients based on either INR > 1.3 or phenprocoumon levels and in 75.8% of DOAC-treated patients based on DOAC levels. Patients suffering an intracranial hemorrhage under VKA showed significantly larger hematoma volumes and a higher in-hospital mortality. Especially in intracerebral hemorrhage, we observed a higher initial severity and numerically greater proportion of early changes towards palliative therapy under VKA, which coincided with a numerically higher case fatality. CONCLUSIONS: We show significantly smaller hematoma volumes for ICH and SDH under DOAC in comparison to VKA and a significantly lower 30-day in-hospital mortality rate of DOAC-ICH, even before the introduction of specific antidotes. These data strongly support the use of DOAC whenever possible in patients requiring OAT. TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov ; Unique identifier: NCT01722786.

Regional anaesthesia in patients on antithrombotic drugs: Joint ESAIC/ESRA guidelines.

BACKGROUND: Bleeding is a potential complication after neuraxial and peripheral nerve blocks. The risk is increased in patients on antiplatelet and anticoagulant drugs. This joint guideline from the European Society of Anaesthesiology and Intensive Care and the European Society of Regional Anaesthesia aims to provide an evidence-based set of recommendations and suggestions on how to reduce the risk of antithrombotic drug-induced haematoma formation related to the practice of regional anaesthesia and analgesia. DESIGN: A systematic literature search was performed, examining seven drug comparators and 10 types of clinical intervention with the outcome being peripheral and neuraxial haematoma. Grading of Recommendations, Assessment, Development and Evaluation (GRADE) was used for assessing the methodological quality of the included studies and for formulating recommendations. A Delphi process was used to prepare a clinical practice guideline. RESULTS: Clinical studies were limited in number and quality and the certainty of evidence was assessed to be GRADE C throughout. Forty clinical practice statements were formulated. Using the Delphi-process, strong consensus (>90% agreement) was achieved in 57.5% of recommendations and consensus (75 to 90% agreement) in 42.5%. DISCUSSION: Specific time intervals should be observed concerning the adminstration of antithrombotic drugs both prior to, and after, neuraxial procedures or those peripheral nerve blocks with higher bleeding risk (deep, noncompressible). These time intervals vary according to the type and dose of anticoagulant drugs, renal function and whether a traumatic puncture has occured. Drug measurements may be used to guide certain time intervals, whilst specific reversal for vitamin K antagonists and dabigatran may also influence these. Ultrasound guidance, drug combinations and bleeding risk scores do not modify the time intervals. In peripheral nerve blocks with low bleeding risk (superficial, compressible), these time intervals do not apply. CONCLUSION: In patients taking antiplatelet or anticoagulant medications, practitioners must consider the bleeding risk both before and after nerve blockade and during insertion or removal of a catheter. Healthcare teams managing such patients must be aware of the risk and be competent in detecting and managing any possible haematomas.

Pharmacokinetics of Direct Oral Anticoagulants in Emergency Situations: Results of the Prospective Observational RADOA-Registry.

BACKGROUND: Direct oral anticoagulants (DOACs) are increasingly used worldwide. Little is known so far about their pharmacokinetics in emergency situations. METHODS: A prospective, observational registry was performed to determine the clinical course in consecutive patients with major bleeding or urgent surgery treated with DOACs. In samples collected as part of routine care DOAC drug concentrations were measured using ultraperformance liquid chromatography-tandem mass spectrometry. Anticoagulant intensity at first presentation and drug half-life (t 1/2), tested in repeat samples, were evaluated. RESULTS: A total of 140 patients were prospectively included. Pharmacokinetic data were available in 94% (132/140) of patients. Note that 67% (89/132) experienced life-threatening bleeding and 33% (43/132) needed an urgent surgery. For pharmacokinetic analysis a total of 605 blood samples was available. Median concentration on admission was 205 ng/mL for rivaroxaban and 108 ng/mL for apixaban. All treatment groups showed a high variation of drug concentrations at baseline. In rivaroxaban-treated patients t ½ was 17.3 hours (95% confidence interval [CI]: 15.4-19.7) without significant difference in both groups (major bleeding: t ½ 16.7 hours, 95% CI: 14.7-19.3; urgent surgery: t ½ 19.7 hours, 95% CI: 15.2-27.9; p = 0.292). In apixaban-treated patients t ½ was 25.0 hours (95% CI: 22.9-27.6) with a longer t ½ after urgent surgery (t 1/2: 30.8 hours; 95% CI: 26.9-36.4) compared with severe bleeding (t 1/2: 20.8 hours; 95% CI: 18.8-23.2; p < 0.001). CONCLUSION: Emergency patients under DOAC treatment show a high variation of anticoagulant concentrations at baseline. Compared with rivaroxaban, apixaban showed a lower median concentration on admission and a longer t ½.