Physician response to implementation of genotype-tailored antiplatelet therapy.

Physician responses to genomic information are vital to the success of precision medicine initiatives. We prospectively studied a pharmacogenomics implementation program for the propensity of clinicians to select antiplatelet therapy based on CYP2C19 loss-of-function variants in stented patients. Among 2,676 patients, 514 (19.2%) were found to have a CYP2C19 variant affecting clopidogrel metabolism. For the majority (93.6%) of the cohort, cardiologists received active and direct notification of CYP2C19 status. Over 12 months, 57.6% of poor metabolizers and 33.2% of intermediate metabolizers received alternatives to clopidogrel. CYP2C19 variant status was the most influential factor impacting the prescribing decision (hazard ratio [HR] in poor metabolizers 8.1, 95% confidence interval [CI] [5.4, 12.2] and HR 5.0, 95% CI [4.0, 6.3] in intermediate metabolizers), followed by patient age and type of stent implanted. We conclude that cardiologists tailored antiplatelet therapy for a minority of patients with a CYP2C19 variant and considered both genomic and nongenomic risks in their clinical decision-making.

Short-acting P2Y12 blockade to reduce platelet dysfunction and coagulopathy during experimental extracorporeal circulation and hypothermia.

BACKGROUND: Extracorporeal circulation (ECC) and hypothermia are routinely used in cardiac surgery to maintain stable circulatory parameters and to increase the ischaemic tolerance of the patient. However, ECC and hypothermia cause platelet activation and dysfunction possibly followed by a devastating coagulopathy. Stimulation of the adenosinediphosphate (ADP) receptor P(2)Y(12) plays a pivotal role in platelet activation. This experimental study tested P(2)Y(12) receptor blockade as an approach to protect platelets during ECC. METHODS: Human blood was treated with the short-acting P(2)Y(12) blocker cangrelor (1 µM, t(1/2)<5 min) or the P(2)Y(12) inhibitor 2-MeSAMP (100 µM) and circulated in an ex vivo ECC model at normothermia (37°C) and hypothermia (28°C). Before and after circulation, markers of platelet activation and of coagulation (thrombin-antithrombin complex generation) were analysed. During hypothermic ECC in pigs, the effect of reversible P(2)Y(12) blockade on platelet function was evaluated by cangrelor infusion (0.075 µg kg(-1) min(-1)). RESULTS: During ex vivo hypothermic ECC, P(2)Y(12) blockade inhibited platelet granule release (P<0.01), platelet-granulocyte binding (P<0.05), and platelet loss (P<0.001), whereas no effects on platelet-ECC binding, platelet CD42bα expression, glycoprotein IIb/IIIa activation, or thrombin-antithrombin complex generation were observed. During hypothermic ECC in pigs, cangrelor inhibited platelet-fibrinogen binding (P<0.05) and ADP-induced platelet aggregation (P<0.001). Platelet function was rapidly restored after termination of cangrelor infusion. CONCLUSIONS: P(2)Y(12) blockade by cangrelor prevents platelet activation during ECC and hypothermia. Owing to its short half-life, platelet inhibition can be well controlled, thus potentially reducing bleeding complications. This novel pharmacological strategy has the potential to reduce complications associated with ECC and hypothermia.

[Volume replacement in intensive care medicine]. / Volumentherapie in der Intensivmedizin.

Volume substitution represents an essential component of intensive care medicine. The amount of fluid administered, the composition and the timing of volume replacement seem to affect the morbidity and mortality of critically ill patients. Although restrictive volume strategies bear the risk of tissue hypoperfusion and tissue hypoxia in hemodynamically unstable patients liberal strategies favour the development of avoidable hypervolemia with edema and resultant organ dysfunction. However, neither strategy has shown a consistent benefit. In order to account for the heavily varying oxygen demand of critically ill patients, a goal-directed, demand-adapted volume strategy is proposed. Using this strategy, volume replacement should be aligned to the need to restore tissue perfusion and the evidence of volume responsiveness. As the efficiency of volume resuscitation for correction of tissue hypoxia is time-dependent, preload optimization should be completed in the very first hours. Whether colloids or crystalloids are more suitable for this purpose is still controversially discussed. Nevertheless, a temporally limited use of colloids during the initial stage of tissue hypoperfusion appears to represent a strategy which uses the greater volume effect during hypovolemia while minimizing the risks for adverse reactions.

[Management of complex thrombocytopenia with thrombelastometry : a case of simultaneous posttransfusion purpura and heparin-induced thrombocytopenia]. / Management einer komplexen Thrombozytopenie mithilfe der Thrombelastometrie : Koinzidenz von posttransfusioneller Purpura und Heparin-induzierter Thrombozytopenie.

The case presented describes the combined onset of heparin-induced thrombocytopenia II (HIT) and post-transfusion purpura (PTP) 5-10 days following exposure to heparin and blood transfusion during aortic dissection repair. On day 4 the platelet count decreased by 40% and D-dimers started to increase again. Despite a low clinical probability for HIT-II at this time (4T score of 3) serological testing was done the next day and yielded a negative test result. Following a transient rise after platelet transfusion another 40% decrease in platelet count occurred on day 8. To increase precision of the 4T score, screening ultrasonography was performed and identified a clinically unapparent jugular vein thrombosis. As this increased the 4T score to 6 points, serological testing was repeated and now showed the presence of HIT-II antibodies. Despite switching from heparin to argatroban the platelet count continued to decrease to <5×10(3)/µl. Conventional clotting tests showed a prolonged prothrombin time and severe hypofibrinogenemia. Because of the female sex, age >50 years, history of pregnancy and transfusion 8 days before, PTP was suspected. The alteration of the plasmatic coagulation, however, could not be explained by PTP. Therefore, disseminated intravascular coagulation (DIC) and interference of argatroban with conventional clotting tests were considered as alternative diagnoses. In order to differentiate between the two alternatives rotational thrombelastometry (ROTEM®) was performed and revealed an increased functional fibrinogen level without signs of hyperfibrinolysis. This argued for an interference of argatroban with the Clauss method of fibrinogen measurement and rendered DIC unlikely. Under suspicion of PTP, treatment with immunoglobulin was initiated and blood transfusions were avoided. Detection of PTP antibodies 1 day later confirmed the combined presence of PTP and HIT-II. As hyperfibrinogenemia compensated for the effects of thrombocytopenia on clot firmness in ROTEM®, anticoagulation with lepirudin was started at 9×10(3) platelets/µl only. The next day the platelet count increased to 32×10(3)/µl and clot firmness returned to normal. No thromboembolic complications and no relevant bleeding were observed. In summary, this case shows for the first time that HIT-II and PTP can occur in parallel in patients with simultaneous exposure to heparin and blood transfusions. Confounding effects of argatroban on conventional clotting tests may mimic DIC under these circumstances and make diagnosis difficult. Careful evaluation of the time-related magnitude in platelet decrease, patient history, course of D-dimers, screening ultrasonography and ROTEM® seem to be helpful to initiate early appropriate therapy before serological test results become available. In contrast to the Clauss method of fibrinogen measurement, assessment of clot firmness in ROTEM® is not influenced by argatroban. Moreover, ROTEM® reveals the compensatory effects of increased functional fibrinogen on clot firmness during severe thrombocytopenia as an important variable for anticoagulation therapy during thrombocytopenia with increased thromboembolic risk.

Thrombelastometry-guided thrombolytic therapy in massive pulmonary artery embolism.

We report a case of a patient who suffered a massive pulmonary embolism with cardiac arrest on post-operative day 4 after a Whipple operation. Despite thrombolytic therapy with the recommended maximal bolus of 50 mg recombinant tissue type plasminogen activator (rt-PA), thrombelastometry showed no signs of fibrinolysis and cardiogenic shock persisted, after only a transient hemodynamic improvement. Not until a repeat bolus of 25 mg rt-PA and an infusion of 50 mg/h did thrombelastometry demonstrate complete fibrinolysis. Although only residual emboli were seen on computed tomography, the patient died secondary to refractory right heart failure. This demonstrates that the standard dosing of thrombolytics may fail in a subgroup of patients, and suggests that thrombelastometry may be useful for early dose adjustment when standard dosing regimens fail.

[Mastocytosis. A challenge in anaesthesiology]. / Mastozytose. Herausforderung in der Anästhesie.

Mastocytosis is a general term for a heterogeneous group of rare disorders. Many agents used in anaesthesia can trigger mast cell degranulation with release of histamine, prostaglandin, tryptase and heparin. Therefore, patients with mastocytosis are high-risk patients when undergoing anaesthesia. The management of these patients in anaesthesia will be discussed on the basis of the literature and illustrated with the discussion of three case reports. A premedication with antihistamines and a glucocorticoid is recommended. For induction of general anaesthesia propofol, etomidate, ketamine, a fentanyl-type opioid, cis-atracurium or pancuronium are recommended. Anaesthesia can be maintained either by a total intravenous technique or with a volatile anaesthetic such as sevoflurane.

[Intraoperative echocardiography: impact on surgical decision-making]. / Intraoperative Echokardiographie : Einfluss auf das chirurgische Management.

Since the introduction of intraoperative echocardiography into clinical practice in the 1970's its use and utility in the perioperative period has become increasingly more evident. Especially in patients undergoing cardiac surgical procedures intraoperative echocardiography has gained great diagnostic importance. Intraoperative transesophageal echocardiography (TEE) and epiaortic ultrasound are two important and complementing diagnostic modalities in this patient population. The clinical information obtained with intraoperative TEE in certain cases might have a direct impact on surgical decision-making and therefore may positively influence patient outcome. In patients undergoing non-cardiac surgical procedures, TEE can be a valuable tool in high-risk patients, in patients experiencing hemodynamic instability or in those suffering intraoperative cardiac arrest. Intraoperative TEE might allow a primary diagnosis of the underlying etiology and facilitate the institution of further therapeutic interventions. In addition TEE can be performed during ongoing cardiopulmonary resuscitation and does not interfere with patient management. This review introduces the clinician to the current evidence of the impact of intraoperative echocardiography on intraoperative surgical decisions during surgical procedures. It helps the clinician to identify indications and realize the potential applications of intraoperative echocardiography.

Audit of motor weakness and premature catheter dislodgement after epidural analgesia in major abdominal surgery.

In a quality improvement audit on epidural analgesia in 300 patients after major abdominal surgery, we identified postoperative lower leg weakness and premature catheter dislodgement as the most frequent causes of premature discontinuation of postoperative epidural infusion. Lower limb motor weakness occurred in more than half of the patients with lumbar epidural analgesia. In a second period monitoring 177 patients, lumbar catheter insertion was abandoned in favour of exclusive thoracic placement for epidural catheters. Additionally, to prevent outward movement, the catheters were inserted deeper into the epidural space (mean (SD) 5.2 (1.5) cm in Period Two vs 4.6 (1.3) cm in Period One). Lower leg motor weakness declined from 14.7% to 5.1% (odds ratio 0.35; 95% confidence interval 0.16-0.74) between the two periods. Similarly, the frequency of premature catheter dislodgement was reduced from 14.5% to 5.7% (odds ratio 0.35; 95% confidence interval 0.17-0.72). With a stepwise logistic regression model we demonstrated that the odds of premature catheter dislodgement was reduced by 43% for each centimetre of additional catheter advancement in Period Two. We conclude that careful audit of specific complications can usefully guide changes in practice that improve success of epidural analgesia regimens.

Monocyte phagocytosis of viable Staphylococcus aureus is impaired by barbiturates, but not by propofol.

BACKGROUND: Barbiturates and propofol are used for deep sedation of patients with elevated intracranial pressure refractory to standard therapeutic regimens. Such patients often suffer from bacterial infections, which are most commonly caused by Staphylococcus aureus. Various interactions of anesthetics with components of the host defense have been documented, but very little is known about the influence on monocytes, which are a first-line defense against bacterial invasion. Therefore, we studied the effects of thiopental, methohexital, and propofol on monocyte phagocytosis using an in vitro whole blood model of viable S. aureus. MATERIALS AND METHODS: Whole blood samples were preincubated with different concentrations of thiopental, methohexital, and propofol. Phagocytosis was stopped at different time points after addition of viable S. aureus. Monocytes then were stained with monoclonal antibodies for flow cytometric analysis of monocyte recruitment (ratio of ingesting monocytes). Furthermore, the fluorescence intensity of ingested bacteria served as semiquantitative measurement of phagocytosis activity. RESULTS: Both barbiturates inhibited monocyte recruitment and phagocytosis activity concentration-dependently, whereas propofol did not affect any of the investigated parameters. At concentrations of 7.6 x10(-3) M thiopental or 1.1 x 10(-3) M methohexital and greater, monocyte recruitment and phagocytosis activity were significantly inhibited. The calculated half-maximum inhibitory concentration (IC50) of thiopental was 8.4 x 10(-3) M for monocyte recruitment and 8.6 x 10(-3) M for phagocytosis activity. The corresponding values for methohexital were 4.1 x 10(-3) M and 1.1 x 10(-3) M, respectively. CONCLUSION: The two barbiturates induce concentration-dependent inhibition of monocyte phagocytosis, whereas propofol is without effect. In combination with previously described effects on granulocyte function, these findings suggest that defense against bacterial infection might be reduced by barbiturates.

[Memantine and Complex Regional Pain Syndrome (CRPS): effects of treatment and cortical reorganisation]. / Memantine und komplexes regionales Schmerzsyndrom (CRPS): Behandlungseffekte und kortikale Reorganisation.

BACKGROUND: In recent studies a central nervous system involvement in the pathogenesis of Complex Regional Pain Syndrome (CRPS) was suggested, stimulating the introduction of central acting drugs. Animal studies have demonstrated an increased expression of the N-methyl-D-aspartate (NMDA) receptors in experimental neuropathic pain. PURPOSE: The aim of this study was to investigate the relationship between NMDA receptor blockers and CRPS. METHOD: Three patients suffering from CRPS of one upper extremity where treated with oral NMDA antagonist Memantine for eight weeks. Patients expressed their pain levels with a visual analog scale ranging from zero to ten at rest and after fist clenching. Furthermore, the range of movement of the fingers and the wrist were documented. To assess force, a pinchmeter and a dynamometer were used. Cortical reorganisation was studied with functional Magnetic Resonance Imaging (fMRI) and Magnetoencephalography (MEG). RESULTS: Six months after treatment with Memantine no rest pain was present in any of the patients. Furthermore, an increase in finger movement was observed after six-month follow-up with no deficits and free movement ranges. Additionally, wrist movement was improved and an increase of force was measured after six months with the dynamometer and the pinchmeter. Moreover the functional impairment, cortical reorganisation was observed in all patients before treatment. These changes returned to a normal pattern after eight weeks of treatment with Memantine. CONCLUSION: These first results demonstrate central nervous system involvement in the development and maintenance of CRPS. The results (functional, pain, fMRI, MEG) after treatment with Memantine indicate the importance of the NMDA receptor system in neuropathic pain syndromes and provide a promising approach for the treatment of CRPS.

[Perioperative echocardiography: basic principles]. / Perioperative Echokardiographie: Technische Grundlagen für den Kliniker.

Over the past decades, echocardiography has undergone a continuous evolution in technology that has promoted its clinical application and acceptance throughout perioperative medicine. These technological advances include improvements in transducer development that permit superior imaging quality and a wider selection of probes for epicardial, epiaortic, and surface echocardiography which can also be used in conjunction with multiplane transesophageal echocardiography. Moreover, the addition of Doppler technology and digital acquisition has secured the role of echocardiography as a valuable and relatively noninvasive diagnostic tool for the assessment of cardiovascular disease and hemodynamic monitoring throughout the perioperative period. Therefore, it has become increasingly important for perioperative physicians to understand the basic principles and underlying fundamental concepts pertaining to the technology and physics of echocardiography, as well as its inherent limitations. The current review outlines the modes and applications of different echocardiographic techniques used in perioperative echocardiography including M-mode, two-dimensional echocardiography, and Doppler assessment of blood flow. In addition, the limitations of these techniques and typical artifacts associated with the perioperative use of echocardiography are described.

[The GABA(A) receptor family: possibilities for the development of better anesthetics]. / Die GABA(A)-Rezeptor-Familie: Möglichkeiten für die Entwicklung besserer Anästhetika.

Clinically used anesthetics show amnestic, sedative, hypnotic and immobilizing properties. On a molecular level these drugs affect several receptors in the cell membrane of neurons. By using genetically engineered mice a linkage can now be made between actions on certain receptors and clinically desired and undesired effects. Experiments show that a certain GABA(A) receptor subtype mediates hypnosis and immobility, whereas another subtype is involved in side-effects like sedation and hypothermia. These findings form the basis for the development of new drugs, acting highly specific and with fewer side-effects.

[Effects of reduced shear stress on inflammatory reactions in vitro. Effects of pathological flow conditions on leukocyte-endothelial interactions and monocyte tissue factor expression in human cell cultures]. / Einfluss verminderter Scherkräfte auf Entzündungsreaktionen in vitro Effekte pathologischer Strömungsbedingungen auf Leukozyten-Endothel-Interaktionen und monozytäre "Tissue-factor-Expression" in humanen Zellkulturen.

BACKGROUND: During malperfusion and inflammation leukocyte adhesion is common. The purpose of this study was to examine the effects of reduced shear stress on leukocyte-endothelial interactions and subsequent inflammatory reactions such as up-regulation of tissue factor. METHODS: Isolated neutrophils and monocytes were co-incubated with human umbilical venous endothelium at 0-3 dynes/cm(2) in a flow chamber. Adhesion and tissue factor expression on adherent leukocytes were examined at various flow conditions. RESULTS: At 2-3 dynes/cm(2) adhesion occurred only on TNFalpha-activated endothelium. Below 1 dyne/cm(2) similarly increased adhesion was also observed on non-activated endothelium. As was observed for leukocyte adhesion, these shear stress-dependent cell interactions also resulted in an up-regulation of tissue factor on adherent monocytes from non-activated co-cultures. CONCLUSION: Apart from additional activators of inflammation, reduced shear forces may directly contribute to inflammation.

[Preoperative evaluation and perioperative management of patients with increased cardiovascular risk]. / Präoperative Evaluation und perioperatives Vorgehen bei kardialen Risikopatienten.

Due to the increasing age in western countries, combined with high rates of major surgical interventions in high-risk patients, perioperative reduction of cardiovascular complications becomes increasingly more important for perioperative physicians. After identifying patients with increased perioperative risk, specific interventions need to be considered to reduce their risk for cardiovascular complications, either by perioperative medical therapy or specific treatment options (e.g. coronary intervention). Several trials have demonstrated an effect of perioperative beta-blocker-therapy in reducing cardiovascular complications among high-risk patients. Additionally, several monitoring techniques are effective in detecting cardiovascular complications. Nevertheless, it remains unclear whether they are associated with a measurable improvement of outcome. Based on the ACC/AHA-guidelines, the present review describes a stepwise approach to surgical patients to identify perioperative risks, based on specific patient related risk factors, the kind of surgery and on the specific setting (emergency versus elective surgery). In addition, strategies to reduce perioperative cardiovascular complications are discussed.

Elimination of linezolid by an in vitro extracorporeal circuit model.

Linezolid is an oxazolidinone antibiotic with activity against important grampositive aerobic bacteria, including nosocomial pathogens. It is not known whether dosage adjustments are necessary in patients treated with continuous renal replacement therapies. This in vitro study was conducted to investigate the elimination of linezolid in an in vitro continuous hemo(dia)filtration model using different filter materials (polysulfone, polyacrylonitrile, polyamide), surface areas, and different modes of renal replacement therapies. Linezolid was measured using HPLC with UV-detection. No adsorption of linezolid to any of the tested membranes was detected. Recovery of linezolid in the ultrafiltrate was 98.2 +/- 10.5% in the filtration mode. During dialysis, recovery was significantly less (87.6 +/- 16.1%; p = 0.02). Linezolid elimination was not altered by filter size, when polysulfone filters with surface areas of 0.7 m2 and 1.3 m2 were tested. In conclusion, the dosage recommendations for linezolid are independent of the filter materials. However, the elimination is significantly higher during hemofiltration compared to dialysis.

[Detection and identification of the pathogenic cause of a brain abscess by molecular genetic methods]. / Erregerdetektion und -identifikation bei einem Hirnabszess durch molekulargenetische Methoden.

Brain abscesses are life-threatening and detection and identification of the causative pathogens are crucial for substantiating the diagnosis and for selecting the optimal antibiotic regimen. In approximately 20% of the patients microbiological cultures of abscess material remain sterile. The polymerase chain reaction (PCR) provides a methodological alternative, but data about the use of broad spectrum PCR assays to detect the causative pathogens in brain abscesses are rare. We report on the case of a 65-years-old patient with a brain abscess caused by Fusobacterium spp., which was only diagnosed by broad spectrum PCR. To our knowledge this is the second report about a brain abscess, where Fusobacterium spp. was identified only by broad spectrum PCR and subsequent DNA sequencing.