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.

High prevalence of pharmacologically induced platelet dysfunction in the acute setting of brain injury.

BACKGROUND: The management of patients with traumatic brain injury (TBI), primary intracerebral hemorrhage (pICH) and primary subarachnoid hemorrhage (pSAH) remains a highly demanding challenge in critical care medicine. Antithrombotic agents are one of the most relevant risk factors for poor outcome. However, in the acute setting of brain injury, information on preexisting medication might not be available. This group of patients is insufficiently characterized regarding pharmacologically induced platelet impairment. METHODS: We retrospectively analyzed consecutive patients with TBI, pICH and pSAH admitted to our department with unknown preexisting medication. The impact of acetylsalicylic acid and ADP-receptor antagonists on platelet function was tested via the Multiplate analyzer. Patients' characteristics, management and the influence of platelet impairment on outcome were evaluated. RESULTS: Within 25 months 103 patients with TBI (61), pICH (32) or pSAH (10) and unknown antithrombotic medication were admitted to our department. In 54 (52.4 %) of the patients reduced platelet function was detected, mainly caused by acetylsalicylic acid. In the TBI group, 30 patients (49.2 %) were identified, while Multiplate analysis detected platelet dysfunction in 19 (59.4 %) subjects in the pICH group and 5 in the pSAH group (50 %). In multivariable analysis the pathological Multiplate result was not associated with worse outcome; however, in our cohort 47 (87 %) patients received hemostatic therapy following detection of impaired platelet function. CONCLUSION: Our results demonstrate the high frequency of pharmacologically impaired platelet function in patients with unknown preexisting medication. Early assessment of platelet function is an important tool to allow optimized treatment in these patients.

Management of direct oral anticoagulants-associated bleeding in the trauma patient.

PURPOSE OF REVIEW: This article emphasizes the differentiated management of direct oral anticoagulants (DOACs)-associated bleeding in trauma patients to generate a severity adjusted treatment protocol. RECENT FINDINGS: The management of DOAC-associated bleeding should take severity, mortality risk, and haemodynamic effects of the trauma-induced bleeding into account. SUMMARY: The different pharmacological properties of DOACs are important for the management of trauma-induced bleeding. Comorbidities like renal impairment and liver dysfunction prolong their half-life. Patients with minor bleeding in stable clinical condition can be managed by a 'wait and see' approach. Moderate bleeding is suggested to be managed by a primarily conservative approach. In life-threatening bleeding, the administration of activated or nonactivated factor concentrates seems justified, together with supportive measures as part of an advanced management protocol. The administration of specific antidotes may be an alternative in the future. A monoclonal antibody to dabigatran (idarucizumab) has recently been approved by the Food and Drug Administration, whereas antidotes to Factor X activated inhibitors (andexanet and aripazine) are still under development. Sufficiently powered studies with clinical and safety outcome measures are still missing for all specific antidotes at this time.

Surgical treatment of intraparenchymal hemorrhage during mechanical circulatory support for heart-failure--a single-centre experience.

BACKGROUND: Cranial intraparenchymal hemorrhage represents a critical complication of mechanical circulatory support requiring constant antithrombotic treatment. Surgery of intraparenchymal hemorrhage under anticoagulation represents a challenge and imposes significant risks for patients. It was the aim to analyse surgical and clinical outcome of patients requiring surgical treatment due to intraparenchymal hemorrhage. METHODS: Patients with mechanical circulatory support requiring surgical therapy due to space-occupying lobar supratentorial or infratentorial hemorrhage from January 1, 2009 to January 1, 2014 were included in our study. Baseline parameters are preoperative International Normalized Ratio (INR) values, postoperative anticoagulation regiment, bleeding size and localization. Co-primary outcome parameters were the extent of hematoma evacuation and the Modified Rankin Scale at discharge from hospital. Secondary outcome parameters included rate of recurrent hemorrhage, rate of revision surgery and in-hospital mortality. RESULTS: Twelve patients (mean age 44 ± 18 years, nine supratentorial-/three infratentorial hemorrhages, 11 left ventricular assist devices, and one extracorporeal membrane oxygenation) were included. Surgical hematoma evacuation was performed in 11 patients, one patient received decompressive hemicraniectomy. Hematoma evacuation was complete in no patients, and partial in 11 patients. Initial INR was 2,7 ± 1,6. Rate of recurrent hemorrhage was 75 %. Revision surgery was performed in three patients achieving partial hematoma evacuation in two patients and complete evacuation in one patient. Modified Rankin Scale at discharge from hospital was six in nine patients (in-hospital mortality of 75 %), five in two patients and four in one patient. CONCLUSIONS: Surgical treatment of life threatening, space-occupying intraparenchymal hemorrhage under mechanical circulation support is of limited efficacy with high rates of recurrent hemorrhage and in-hospital mortality. We provide additional data that postponing anticoagulation is feasible and may lead to improved clinical outcome and survival.

[Intracranial hypertension - Therapeutic options]. / Der erhöhte intrakranielle Druck - Therapiemaßnahmen.

Increased intracranial pressure can be the result of different intracranial pathologies. Sustained intracranial pressure above 20-25 mmHg may cause secondary brain injury by impaired cerebral perfusion or direct pressure with neuronal injury, with in consequence deterioration of neurological outcome. A main cause of critically increased intracranial pressure is traumatic brain injury. Most treatment strategies for increased intracranial pressure were developed and studied on these patients. Most of them were transferred to other pathologies with increased intracranial pressure.Treatment is based on general measures, which can be escalated for medical and surgical options in case of failure to sufficiently decrease intracranial pressure below the established threshold. Despite its enormous medical and socio-economical relevance, the evidence for most treatment strategies of intracranial hypertension, though published in guidelines, is weak.

[Multimodal neuromonitoring - indications and methodes]. / Der erhöhte intrakranielle Druck - Multimodales Neuromonitoring - Indikationen und Methoden.

Managing patients after severe traumatic brain injury and aneurysmal subarachnoid hemorrhage is a challenging task of modern intensive care. Most patients do require sedation for mechanical ventilation due to respiratory distress or treatment of increased intracranial pressure. Besides standard ICP monitoring, a variety of continuous monitoring technologies for bedside use exists. The paper discusses the 5 methods most frequently used and their significance for multimodal neuromonitoring.

[Intracranial hypertension in various brain diseases - Specific therapy and outcome]. / Der erhöhte intrakranielle Druck - Therapiestrategien und Outcomerelevanz bei unterschiedlichen neurologischen und neurochirurgischen Krankheitsbildern.

Elevated intracranial pressure (ICP) in various brain diseases has for long time been treated according to guidelines for traumatic brain injury. First data of randomized study reveal, that specific treatment options like decompressive craniectomy, hyperosmotic agents, hyperventilation, hypothermia and steroids should have specific indications to control elevated ICP in future. In general, optimal ICP-treatment should also target sufficient cerebral perfusion and oxygenation.

Dynamic thromboembolic left ventricular outflow tract obstruction after aggressive procoagulant treatment in hemorrhagic shock: a case report.

BACKGROUND: In cases of hypertrophic obstructive cardiomyopathy (HOCM), the systolic anterior motion of the mitral valve apparatus results in an obstruction of the left ventricular outflow tract (LVOT), which is known as the SAM [systolic anterior motion] phenomenon. Hypothetically, a pathological obstruction of the LVOT of a different etiology would result in a comparable hemodynamic instability, which would be refractory to inotrope therapy, and may be detectable through echocardiography. CASE PRESENTATION: We observed a severely impaired left ventricular function due to a combination of a thrombotic LVOT obstruction and distinctive mitral regurgitation in a 56-year-old Caucasian, female patient after massive transfusion with aggressive procoagulant therapy. Initially, the patient had to be resuscitated due to cardiac arrest after a long-distance flight. The resuscitation attempts in combination with lysis therapy due to suspected pulmonary artery embolism were initially successful but resulted in traumatic liver injury, hemorrhagic shock and subsequent acute respiratory distress syndrome (ARDS). Oxygenation was stabilized with veno-venous extracorporeal membrane oxygenation (ECMO), but the hemodynamic situation deteriorated further. Transesophageal echocardiography (TEE) showed a massive, dynamic LVOT obstruction. Two thrombi were attached to the anterior leaflet of the mitral valve, resulting in a predominantly systolic obstruction. Unfortunately, the patient died of multiple-organ failure despite another round of lysis therapy and escalation of the ECMO circuit to a veno-venoarterial cannulation for hemodynamic support. CONCLUSION: Massive transfusion with aggressive procoagulant therapy resulted in mitral valve leaflet thrombosis with dynamic, predominantly systolic LVOT obstruction, comparable to the SAM phenomenon. The pathology was only detectable with a TEE investigation.

Mortality associated with administration of high-dose tranexamic acid and aprotinin in primary open-heart procedures: a retrospective analysis.

INTRODUCTION: Antifibrinolytic agents are commonly used during cardiac surgery to minimize bleeding. Because of safety concerns, aprotinin was withdrawn from the market in 2007. Since then, tranexamic acid (TXA) has become the antifibrinolytic treatment of choice in many heart centers. The safety profile of TXA has not been extensively studied. Therefore, the aim of this study was to evaluate safety and efficiency of TXA compared with aprotinin in cardiac surgery. METHODS: Since July 1, 2006, TXA has been administered at a dose of 50 mg/kg tranexamic acid before cardiopulmonary bypass (CPB) and 50 mg/kg into the priming fluid of the CPB. Prior to this, all patients were treated with aprotinin at a dose of 50,000 KIU per kilogram body weight. Safety was evaluated with mortality, biomarkers, and the diagnosis of myocardial infarction, ischemic stroke, convulsive seizures, and acute renal failure in the intensive care unit (ICU), intermediate care unit (IMCU), and hospital stay. Efficiency was evaluated by the need for transfusion of blood products and total postoperative blood loss. RESULTS: After informed consent, 893 patients were included in our database (557 consecutive patients receiving aprotinin and 336 patients receiving TXA). A subgroup of 320 patients undergoing open-heart procedures (105 receiving TXA and 215 receiving aprotinin) was analyzed separately. In the aprotinin group, a higher rate of late events of ischemic stroke (3.4% versus 0.9%; P = 0.02) and neurologic disability (5.8% versus 2.4%; P = 0.02) was found. The rate of postoperative convulsive seizures was increased in tendency in patients receiving TXA (2.7% versus 0.9%; P = 0.05). The use of TXA was associated with higher cumulative drainage losses (PANOVA < 0.01; Ptime < 0.01) and a higher rate of repeated thoracotomy for bleeding (6.9% versus 2.4%; P < 0.01). In the subgroup of patients with open-chamber procedures, mortality was higher in the TXA group (16.2% TXA versus 7.5% aprotinin; P = 0.02). Multivariate logistic regression identified EURO score II and CPB time as additional risk factors for this increased mortality. CONCLUSIONS: The use of high-dose TXA is questioned, as our data suggest an association between higher mortality and minor efficiency while the safety profile of this drug is not consistently improved. Further confirmatory prospective studies evaluating the efficacy and safety profile of TXA are urgently needed to find a safe dosage for this antifibrinolytic drug.

Microtransplantation of dopaminergic cell suspensions: further characterization and optimization of grafting parameters.

Intracerebral transplantation of dopaminergic (DA) cells is currently further explored as a potential restorative therapy for Parkinson's disease (PD). However, before they can be considered for a more widespread clinical use a number of critical issues have to be resolved, including an optimized transplantation protocol. This study has been performed in a rat 6-hydroxydopamine model of PD and is based on the microtransplantation approach. The results demonstrate a reduced survival (threefold) for a single cell suspension of E14 rat ventral mesencephalon compared to a fragment suspension when a metal cannula is used for implantation. However, fragment suspensions result in a more variable graft survival and ectopically placed cells along the implantation tract. When a glass capillary is used for implantation, the survival of the single cell suspension (so-called "micrograft") improved by fourfold (vs. single cells/metal cannula) and is superior to the combination of the metal cannula and fragment suspension (+40%). The micrografts show a reduced variability in DA neuron survival as well as fewer ectopically placed cells. Moreover, the implantation time can significantly be reduced from 19 to 7 min in micrografted animals without a compromise in DA graft survival and functional behavioral outcome. Using the microtransplantation approach graft size can be tailored effectively by varying the density of the final cell suspension at least between 11,000 and 320,000 cells/microl, resulting in comparable survival of tyrosine hydroxylase (TH)-positive neurons in the range of 2-4%. With this approach no more than 100 surviving TH-positive neurons are necessary to produce functional effects in the amphetamine-induced rotation test. Interestingly, we found that DA micrografts into lesion striatum present 20% higher survival rates of TH neurons in comparison to the intact striatum. In summary, these results provide further evidence for the usefulness of the microtransplantation approach and allow for a more precise and tailored adaptation of the implantation parameters for further studies on DA, and possibly also other neural-, glial-, and stem cell-derived grafts.

[Bleeding Management under Direct Oral Anticoagulants (DOAC)]. / Blutungsmanagement unter direkten oralen Antikoagulanzien (DOAK).

Despite the widespread use of DOAC and recommendations of regulatory agencies and first consensus meetings on handling of bleeding situation under DOAC uncertainty still exists. In case of mild bleeding, the medical care of these patients and the delay of the next dose is advised. A laboratory analysis is indicated i. e. in case of known higher grade liver and kidney failure. The administration of factor concentrates or antidots is not indicated in this situation. In case of moderate to severe bleeding, the primary focus lies on stabilization of cardiopulmonary and circulatory function and parallel on the treatment depending on the localization of the bleeding source. In life-threatening bleeding in addition to the measures of hemodynamic stabilization a special haemostasis management may be required. In severe life-threatening bleeding treatment algorithms should be applied. In factor Xa-inhibitor-associated bleeding the use of factor concentrates (procoagulants), i. e. PCC in addition to unspecific measures, is indicated, as the direct antagonist andexanet alpha has not been approved in the EU. In contrast, the specific antagonist idarucizumab for acute dabigatran reversal is available in Germany.

Update on Direct Oral AntiCoagulants (DOACs).

Recent findings require an update of previous recommendations for the perioperative use of Direct Oral AntiCoagulants (DOACs). A break in preoperative treatment of 24-96 hours is recommended based on the pharmacokinetic profiles of DOACs and depends on individual patient characteristics, their renal and possibly liver function, and their surgery-related risk of bleeding. In cases of renal or hepatic insufficiency, whether to extend the preoperative interruption of IIa- and Xa-inhibitors is a clinical decision that must be reached on an individual patient basis. In cases of epidural or spinal anaesthesia, more conservative pausing-intervals are recommended due to the risk of persistent neurologic deficits (e.g., paraplegia) following the development of spinal subdural and epidural haematomas. Elective surgery should be postponed according to these recommendations. Preoperative "bridging" with LMWH (more precisely referred to as "switching") should be omitted due to a significantly increased risk of bleeding. In addition, the incidence of perioperative thromboembolic risks, such as DVT, PE, and stroke, are no different whether interruption or "switching" is undertaken. Postoperatively, the DOACs can be reinstituted within the first 24 hours. In cases of major surgery or if there is a higher risk of bleeding, resumption of DOACS should only begin after 24-72 hours. In patients with an elevated thromboembolic risk, transient postoperative LMWH administration can be recommended during this period.Interaction of DOACs with other drugs usually occurs during the absorption, transport and elimination of these drugs. Therefore, substance- specific restrictions and recommendations should be observed during these times. In everyday clinical practice, webbased, independent information portals on drug-interactions are very helpful in providing safe and rapid information about potential interactions when DOACs are used in combination with other drugs, especially during perioperative management.Non-adherence to medications is a worldwide problem that has dangerous and costly consequences. Present data suggest that persistence is the primary factor that supports adherence. Despite the adherence data presented in the DOACS approval studies (e.g., persistence in the treatment of acute venous thromboembolism has been reported to be between 94-99%), the first registries and meta-analyses provide sobering results regarding the incidence of persistence and the success rate of interventions designed to improve adherence with DOACs in cases of long-term usage.

A calcium-containing electrolyte-balanced hydroxyethyl starch (HES) solution is associated with higher factor VIII activity than is a non-balanced HES solution, but does not affect von Willebrand factor function or thromboelastometric measurements--results of a model of in vitro haemodilution.

BACKGROUND: Hydroxyethyl starch (HES) is known to impair blood coagulation. The impact of calcium-containing, balanced carrier solutions of HES on coagulation is controversial. We investigated the effects of increasing degrees of haemodilution with modern 6%, electrolyte-balanced HES vs non-balanced HES on coagulation in vitro, and compared the balanced HES to a balanced crystalloid solution for an internal control. MATERIALS AND METHODS: Blood samples from ten healthy volunteers were diluted in vitro by 20%, 40% and 60% with either calcium-containing balanced 130/0.42 HES, non-balanced 130/0.4 HES or balanced crystalloid. In all samples, blood counts, prothrombin time ratio, activated partial thromboplastin time, ionized calcium, factor VIII activity, von Willebrand factor antigen, von Willebrand factor collagen binding activity, and von Willebrand factor activity were determined, and activated rotational thromboelastometry (EXTEM and FIBTEM assays) was performed. RESULTS: Haemodilution impaired coagulation in a dilution-dependent manner as determined by both conventional laboratory assays and thromboelastometry. Ionized calcium increased with balanced HES (p≤0.004), but decreased with non-balanced HES (p≤0.004). Prothrombin time ratio (p≤0.002) and factor VIII levels (p=0.001) were better preserved with balanced HES than with non-balanced HES in dilutions ≥40%. Thromboelastometry showed no differences between values in blood diluted with the balanced or non-balanced HES. DISCUSSION: In vitro, a balanced calcium-containing carrier solution of 6% HES 130/0.42 preserved coagulation better than did non-balanced HES 130/0.4 as quantified by conventional coagulation assays, but not in activated thromboelastometry. One explanation could be the increased ionized calcium levels after dilution with calcium-containing carrier solutions.

Pattern of long-term sensorimotor recovery following intrastriatal and--accumbens DA micrografts in a rat model of Parkinson's disease.

The functional restorative capacity of fetal dopaminergic (DA) transplants is governed by a number of critical parameters including graft location, survival of DA neurons, and transplantation technique. In addition, there is an ongoing controversy whether "too much" or "too little" survival of DA neurons is responsible for the incomplete functional recovery observed in some transplanted Parkinson's disease (PD) patients. Here we investigated two implantation sites, the nucleus accumbens (NAc) and the caudate-putamen unit (CPU), and two different graft distributions within the CPU, i.e., two 0.75 microL deposits (CPU-2) versus six 0.25 microL deposits (CPU-6) in a rat model of PD. Grafts were derived from E14 rat ventral mesencephalon and the long-term functional outcome was evaluated with a wide range of complex-sensorimotor behavioral tests. The data show that forelimb stepping, balancing behavior, and skilled forelimb reaching behavior was more restored in CPU-6-grafted animals as compared to CPU-2 animals, although the number surviving dopaminergic neurons and dopamine release were similar in the two groups. Furthermore, a correlation analysis revealed a number of inverse relationships between the rate of DA neuron survival and sensorimotor performances, e.g., for skilled forelimb use. DA grafts placed into the NAc induced a partial recovery in drug-induced rotation tests but failed to restore any of the other sensorimotor behaviors tested. Taken together, these data have important implications both for a better understanding of the complex functional graft-host interactions as well as for the further optimization of clinical neural transplantation strategies in neurodegenerative diseases.