[Short version of the 2nd edition of the German-Austrian S3 guidelines "Cardiogenic shock complicating myocardial infarction-Diagnosis, monitoring and treatment"]. / Kurzversion der 2. Auflage der deutsch-österreichischen S3-Leitlinie "Infarkt-bedingter Kardiogener Schock ­ Diagnose, Monitoring und Therapie".

BACKGROUND: The present guidelines ( http://leitlinien.net ) focus exclusively on cardiogenic shock due to myocardial infarction (infarction-related cardiogenic shock, ICS). The cardiological/cardiac surgical and the intensive care medicine strategies dealt with in these guidelines are essential to the successful treatment and survival of patients with ICS; however, both European and American guidelines on myocardial infarction and heart failure and also position papers on cardiogenic shock focused mainly on cardiological aspects. METHODS: Evidence on the diagnosis, monitoring and treatment of ICS was collected and recommendations compiled in a nominal group process by delegates of the German Cardiac Society (DGK), the German Society for Medical Intensive Care Medicine and Emergency Medicine (DGIIN), the German Society for Thoracic and Cardiovascular Surgery (DGTHG), the German Society for Anaesthesiology and Intensive Care Medicine (DGAI), the Austrian Society for Internal and General Intensive Care Medicine (ÖGIAIM), the Austrian Cardiology Society (ÖKG), the German Society for Prevention and Rehabilitation of Cardiovascular Diseases (DGPR) and the German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI), under the auspices of the Working Group of the Association of Medical Scientific Societies in Germany (AWMF). If only poor evidence on ICS was available, general study results on intensive care patients were inspected and presented in order to enable analogue conclusions. RESULTS: A total of 95 recommendations, including 2 statements were compiled and based on these 7 algorithms with defined instructions on the course of treatment.

[Dual platelet inhibitors in intensive care units]. / Duale Plättchenhemmung in der Intensivmedizin.

BACKGROUND: The introduction of clopidogrel was a milestone in the development of modern antiplatelet therapy. However, the shortcomings in the pharmacokinetics of clopidogrel have led to the development of alternative substances. CURRENT CONCEPT: The two new drugs prasugrel and ticagrelor were included in the current guidelines for the treatment of patients with acute coronary syndrome. These potent platelet inhibitors, however, are associated with an increased rate of bleeding events, which is of particular importance in critically ill patients. However, the new platelet inhibitors are less effective in patients with cardiogenic shock or patients treated with therapeutic hypothermia. FUTURE: Recent studies underscore the assessment of the net clinical benefit in patient management. Since there is only a thin line between efficacy and safety in critically ill patients, future studies for risk stratification of antiplatelet therapy in terms of personalized medicine are mandatory.

Clinical implications of drug-drug interactions with P2Y12 receptor inhibitors.

Polypharmacy in patients undergoing coronary artery stenting or in those presenting with an acute coronary syndrome is common. Nevertheless, the risk of drug-drug interactions in patients treated simultaneously with P2Y12 receptor inhibitors is less well considered in routine clinical practice. Whereas the irreversible P2Y12 receptor inhibitors clopidogrel and prasugrel are prodrugs requiring cytochrome P450 (CYP) enzymes for metabolic activation, such activation is not necessary for the direct-acting reversible P2Y12 receptor inhibitor ticagrelor. Several drugs frequently used in cardiology have been shown to interact with the metabolism of P2Y12 receptor inhibitors in pharmacodynamic studies. Whereas several drug-drug interactions have been described for clopidogrel and ticagrelor, prasugrel seems to have a low potential for drug-drug interactions. The clinical implications of these interactions have raised concern. In general, concomitant administration of P2Y12 receptor antagonists and strong inhibitors or inducers of CYP3A/CYP2C19 should be performed with caution in patients treated with clopidogrel/ticagrelor. Under most circumstances, clinicians have the option of prescribing alternative drugs with less risk of drug-drug interactions when used concomitantly with P2Y12 receptor inhibitors.

Phenotyping vs. genotyping for prediction of clopidogrel efficacy and safety: the PEGASUS-PCI study.

BACKGROUND: Prognostic values of genotyping and phenotyping for assessment of clopidogrel responsiveness have been shown in independent studies. OBJECTIVES: To compare different assays for prediction of events during long-term follow-up. METHODS: In this prospective cohort study polymorphisms of CYP2C19*2 and CYP2C19*17 alleles, vasodilator-stimulated phosphoprotein phosphorylation (VASP) assay, multiple electrode aggregometry (MEA), cone and platelet analyser (CPA) and platelet function analyser (PFA-100) were performed in 416 patients undergoing percutaneous coronary intervention. The rates of events were recorded during a 12-month follow-up. RESULTS: Platelet aggregation by MEA predicted stent thrombosis (2.4%) better (c-index = 0.90; P < 0.001; sensitivity = 90%; specificity = 83%) than the VASP assay, CPA or PFA-100 (c-index < 0.70; P > 0.05; sensitivity < 70%; specificity < 70% for all) or even the CYP2C19*2 polymorphism (c-index < 0.56; P > 0.05; sensitivity = 30%; specificity = 71%). Survival analysis indicated that patients classified as poor responders by MEA had a substantially higher risk of developing stent thrombosis or MACE than clopidogrel responders (12.5% vs. 0.3%, P < 0.001, and 18.5% vs. 11.3%, P = 0.022, respectively), whereas poor metabolizers (CYP2C19*1/*2 or *2/*2 carriers) were not at increased risks (stent thrombosis, 2.7% vs. 2.5%, P > 0.05; MACE, 13.5% vs. 12.1%, P = 0.556). The incidence of major bleedings (2.6%) was numerically higher in patients with an enhanced vs. poor response to clopidogrel assessed by MEA (4% vs. 0%) or in ultra-metabolizers vs. regular metabolizers (CYP2C19*17/*17 vs. CYP2C19*1/*1; 9.5% vs. 2%). The classification tree analysis demonstrated that acute coronary syndrome at hospitalization and diabetes mellitus were the best discriminators for clopidogrel responder status. CONCLUSIONS: Phenotyping of platelet response to clopidogrel was a better predictor of stent thrombosis than genotyping.

Multiple electrode aggregometry predicts stent thrombosis better than the vasodilator-stimulated phosphoprotein phosphorylation assay.

BACKGROUND AND AIM: The prognostic value of the vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay and multiple electrode aggregometry (MEA) for thrombotic adverse events has been shown in independent studies. As no direct comparison between the two methods has been made so far, we investigated which laboratory approach has a better predictive value for stent thrombosis. METHODS: The VASP phosphorylation assay and MEA were performed in 416 patients with coronary artery disease undergoing percutaneous coronary intervention. The rate of stent thrombosis was recorded during a 6-month follow-up. RESULTS: Definite stent thrombosis occurred in three patients (0.7%) and probable stent thrombosis in four (1%). Receiver operating characteristic (ROC) analysis demonstrated that MEA distinguishes between patients with or without subsequent stent thrombosis better than the VASP phosphorylation assay: the area under the ROC curve was higher for MEA (0.92; P=0.012) than for the VASP phosphorylation assay (0.60; P=0.55). At equal levels of sensitivity (100%), the specificity was greater for MEA than for the VASP phosphorylation assay (86% vs. 37%). Stent thrombosis occurred in 9% of patients with platelet hyperreactivity in MEA, who were simultaneously clopidogrel non-responders in the VASP phosphorylation assay. Interestingly, clopidogrel non-responders in the VASP phosphorylation assay without platelet hyperreactivity in MEA did not suffer from stent thrombosis. CONCLUSIONS: Platelet hyperreactivity in MEA might be a better risk predictor for stent thrombosis than the assessment of the specific clopidogrel effect with the VASP phosphorylation assay.

Hemodynamic effects of a continuous infusion of levosimendan in critically ill patients with cardiogenic shock requiring catecholamines.

BACKGROUND: Levosimendan, a novel inodilator, has been shown to improve hemodynamic function in patients with decompensated heart failure with preserved arterial blood pressure. Data on its use in patients with cardiogenic shock are rare. The present series describes the 24-h hemodynamic effects of levosimendan as add-on therapy in desperately ill patients with cardiogenic shock requiring catecholamines. METHODS: Ten patients with cardiogenic shock received levosimendan as continuous infusion of 0.1 microg kg(-1) min(-1) for 24 h. The patients were otherwise unselected. Hemodynamic measurements were routinely performed at baseline (time 0) and at 1, 8, 16 and 24 h after start of levosimendan (LS) using a Swan-Ganz thermodilution catheter. RESULTS: During the levosimendan infusion there was a significant increase in cardiac index from 1.8 +/- 0.4 to 2.4 +/- 0.6 L*min-1*m-2 (P = 0.023) and a significant decrease in systemic vascular resistance from 1559 +/- 430 to 1109 +/- 202 dyn*s*cm-5 (P = 0.001), respectively. Changes in catecholamine dose, and in systolic and diastolic blood pressure were not significant. Given the individual response to LS, 8/10 patients showed an increase in left ventricular stroke work index under reduced or roughly unchanged preload conditions after 8 h. CONCLUSION: This series shows that a LS infusion is feasible and able to improve hemodynamics in severely compromized, critically ill patients with cardiogenic shock requiring catecholamine therapy. Its potential advantages when compared with other inotropes are unclear. To clarify the potential role of LS in this clinical setting randomized controlled trials on hemodynamic and mortality endpoints are needed.

Prophylactic anticoagulation with enoxaparin: Is the subcutaneous route appropriate in the critically ill?

BACKGROUND: Subcutaneously administered low-molecular-weight heparins are widely used for prevention of venous thromboembolism. The appropriateness of the subcutaneous route in critically ill patients has never been established. OBJECTIVE: To determine anti-Xa activities in critically ill patients and in noncritically ill patients receiving prophylactic doses of subcutaneous enoxaparin. DESIGN: Prospective, controlled, open-labeled study. SETTING: Tertiary medical-cardiologic-postoperative intensive care unit and a general medical ward at a university hospital. PATIENTS: A total of 16 intensive care unit patients (group 1; age, 61.1 +/- 16 yrs; male/female ratio, 7/9; Acute Physiology and Chronic Health Evaluation II score, 20.9 +/- 7; mechanical ventilation, n = 15; vasopressors, n = 13) and 13 noncritically ill medical patients (group 2; age, 61.7 +/- 9 yrs; male/female ratio, 7/6) were studied. Body mass index (25.7 +/- 5 vs. 24 +/- 6 kg/m2, p = not significant) was comparable and serum creatinine levels (0.83 +/- 0.25 vs. 1.07 +/- 0.3 mg/dL, group 1 vs. 2) were within the normal range in both groups. Patients with impaired renal function, receiving hemofiltration, or requiring therapeutic anticoagulation were not eligible. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Anti-Xa activities were determined at 0, 1, 3, 6, and 12 hrs after a single daily subcutaneous dose of 40 mg enoxaparin on day 1 and at 3 hrs after 40 mg of enoxaparin on days 2-5. Mean anti-Xa levels at 0 to 12 hrs were consistently lower in group 1 compared with group 2 by analysis of variance (p =.001 between groups and over time), as was the area under the curve at 0 to 12 hrs (2.6 +/- 1 vs. 4.2 +/- 1.7 units x mL(-1) x hr(-1), group 1 vs. 2, p =.008). Significant differences in anti-Xa activity were also found on days 2-5 (p =.001). Peak anti-Xa activities at 3 hrs after administration were negatively correlated with the body mass index (r = -.41, p <.03). No correlation was found between the anti-Xa activity at 3 hrs and the dose of norepinephrine (r =.12, p =.7). CONCLUSION: Critically ill patients with normal renal function demonstrated significantly lower anti-Xa levels in response to a single daily dose of subcutaneous enoxaparin when compared with medical patients in the normal ward.

Plasminogen activator inhibitor type 1 and outcome after successful cardiopulmonary resuscitation.

OBJECTIVE: Patients after successful cardiopulmonary resuscitation have been shown to exhibit elevated plasma concentrations of plasminogen activator inhibitor (PAI) type 1, the main circulating antifibrinolytic protein. It has been suggested that elevations in PAI-1 contribute to cerebral no-reflow after successful cardiopulmonary resuscitation. We analyzed whether PAI-1 concentrations might predict cerebral outcome after cardiopulmonary resuscitation. DESIGN: Prospective, controlled study. SETTING: Intensive care unit at a university hospital. PATIENTS: Thirty-five patients after successful cardiopulmonary resuscitation and 35 control patients who were not critically ill. INTERVENTIONS: Blood sampling for determination of plasma concentrations of active and total PAI-1 antigen. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of total and active PAI-1 antigen on the second day after successful cardiopulmonary resuscitation were significantly higher in patients after cardiopulmonary resuscitation than in controls (p <.0001) and were unrelated to duration of cardiopulmonary resuscitation. Both active and total PAI-1 antigen were higher in patients who developed acute renal failure after cardiopulmonary resuscitation. Patients with an unfavorable cerebral outcome after cardiopulmonary resuscitation had higher total PAI-1 antigen concentrations compared with patients with good outcome after cardiopulmonary resuscitation (p =.026). We identified 180 ng/mL as the best cutoff value for total PAI-1 antigen with respect to cerebral outcome (chi-square 11.8, p =.001). In a logistic regression analysis, only systemic inflammatory response syndrome (p =.028), acute renal failure after cardiopulmonary resuscitation (p =.017), and cardiopulmonary resuscitation duration >15 mins (p =.042) were significantly and independently associated with cerebral outcome after cardiopulmonary resuscitation. Total PAI-1 antigen reached only borderline significance (p =.058) but nevertheless slightly improved the correct prediction of cerebral outcome after cardiopulmonary resuscitation. CONCLUSIONS: Acute renal failure after cardiopulmonary resuscitation, systemic inflammatory response syndrome, and cardiopulmonary resuscitation duration are better predictors of cerebral outcome after cardiopulmonary resuscitation than PAI-1 antigen, but determination of total PAI-1 antigen nevertheless might improve the early prediction of cerebral outcome after cardiopulmonary resuscitation. Whether elevated PAI-1 concentrations, possibly via prothrombogenic/antifibrinolytic effects, contribute causally to cerebral no-reflow and acute renal failure after cardiopulmonary resuscitation remains to be clarified.

Amiodarone versus diltiazem for rate control in critically ill patients with atrial tachyarrhythmias.

OBJECTIVE: To compare the rate-lowering effect of diltiazem and two amiodarone regimens in critically ill patients with recent-onset atrial tachyarrhythmias. DESIGN: Prospective, randomized, controlled study. SETTING: Medical cardiologic intensive care unit in a university hospital. PATIENTS: Sixty critically ill patients (Acute Physiology and Chronic Health Evaluation [APACHE] III score 70 +/- 30, age 67 +/- 10 yrs). INTERVENTIONS: Patients with atrial fibrillation (n = 57), atrial flutter (n = 2), or atrial tachycardia (n = 1, and a heart rate consistently >120 beats/min over 30 mins were randomly assigned to one of three intravenous treatment regimens. Group 1 received diltiazem in a 25-mg bolus followed by a continuous infusion of 20 mg/hr for 24 hrs, group 2 received amiodarone in a 300-mg bolus, and group 3 received amiodarone in a 300-mg bolus followed by 45 mg/hr for 24 hrs. MEASUREMENTS AND MAIN RESULTS: The primary study end point was a >30% rate reduction within 4 hrs. The secondary study end point was a heart rate <120 beats/min (a patient was considered to have uncontrolled tachycardia if heart rate was >120 beats/min 4 hrs after study drug). The primary study end point was achieved in 14/20 (70%), 11/20 (55%), and 15/20 (75%) of patients in groups 1, 2, and 3, respectively (chi2 = 1.95, p =.38). Uncontrolled tachycardia was more frequently observed in group 2 (0/20, 9/29 [55%], and 1/20 [5%] of patients in groups 1, 2, and 3, respectively; chi2 = 17, p =.00016). In patients achieving tachycardia control, diltiazem showed a significantly better rate reduction (p =.0001 group 1 vs. group 3, p =.0001 over time; p =.0001 group 1 vs. group 2, p =.001 over time) when compared with the amiodarone groups. Premature drug discontinuation due to hypotension was required significantly more often in group 1 (6/20 [30%], 0/20, and 1/20 [5%] for groups 1, 2, and 3, respectively; chi2 = 10, p =.01). CONCLUSION: Sufficient rate control can be achieved in critically ill patients with atrial tachyarrhythmias using either diltiazem or amiodarone. Although diltiazem allowed for significantly better 24-hr heart rate control, this effect was offset by a significantly higher incidence of hypotension requiring discontinuation of the drug. Amiodarone may be an alternative in patients with severe hemodynamic compromise.

Effects of milrinone on pulmonary gas exchange in catecholamine-dependent heart failure.

Hemodynamic benefits of milrinone administration are accompanied by adverse effects on arterial oxygenation in mechanically ventilated patients with end-stage heart failure. Particular attention should be focused on pulmonary gas exchange variables after initiation of milrinone treatment in the critically ill patient.

Milrinone therapy in catecholamine-dependent critically ill patients with heart failure.

BACKGROUND: Treatment with the PDE-III inhibitor milrinone improves hemodynamics in patients with heart failure. We examined whether therapy with milrinone is safe and effective in critically ill patients with catecholamine-dependent heart failure and whether treatment with milrinone facilitates weaning from prolonged catecholamine therapy. METHODS: Twenty adult patients with reduced left ventricular function and prolonged (7+/-4 days) catecholamine therapy in whom attempts at catecholamine weaning had failed were examined. Patients were prospectively randomised either to group A (addition of a fixed dose of 0.5 microg x kg(-1) x min(-1) milrinone to catecholamine therapy) or to group B (continued catecholamine therapy without milrinone). Dobutamine and norepinephrine treatment and fluid intake were titrated according to predefined hemodynamic goals. Hemodynamic parameters, fluid requirements and catecholamine dose were monitored. RESULTS: After 24 h of study treatment goup A showed a significant increase in cardiac index (2.2+/-0.4 1 min(-1) x m(-2) to 2.7+/-0.51 min(-1) x m(-2); P<0.005), a decrease in systemic vascular resistance (1,427+/-609 dyn x s x cm(-5) to 951+/-184 dyn x s x cm(-5); P<0.005), required lower doses of dobutamine (5.9+/-4.2 microg x kg(-1) x min(-1) to 2.2+/-3.3 microg x kg(-1) x min(-1); P<0.02), but showed a tendency for higher vasoconstrictor (0.14+/-0.16 microg x kg(-1) x min(-1) to 0.29+/-0.43 microg x kg(-1) x min(-1); P=n.s.) and fluid requirements (+1,404+/-2,257 ml/24 h to +2,508+/-1,873 ml/ 24 h; P=n.s.). No significant changes occurred in group B. Weaning from catecholamine therapy was more often achieved in group A and more milrinone treated patients were discharged alive from the ICU (80% vs. 30%; P<0.05). CONCLUSIONS: Milrinone improves central hemodynamics and may facilitate weaning from prolonged catecholamine support in critically ill patients with heart failure. Its administration in this subset of critically ill patients is safe, but eventually is associated with additional vasoconstrictor and fluid requirements.

Stereolithographic biomodeling to create tangible hard copies of cardiac structures from echocardiographic data: in vitro and in vivo validation.

OBJECTIVES: This study investigated the feasibility, accuracy and clinical potential of creating polymer hard copies of echocardiographic data using stereolithography. BACKGROUND: Three-dimensional (3D) echocardiography has so far been limited by the need to display reconstructed 3D objects on a two-dimensional screen. Thus, tangible stereolithographic polymer models created from echocardiographic data could enhance our spatial perception of cardiac anatomy and pathology. METHODS: Hard-copy replicas of water-filled latex balloon phantoms (n = 7) and porcine liver specimens (n = 12) were generated from echocardiographic images using stereolithography (computerized laser polymerization). In addition, we created 24 models of the mitral valve from 12 transesophageal studies (normal = 6, mitral stenosis n = 4, prolapse/flail leaflet n = 8, annular dilation n = 2, leaflet restriction n = 2 and following mitral valve repair n = 2). RESULTS: Excellent agreement was found for comparison of volumes (r = 0.98, SEE = 3.46 mm3, mean difference = 0.25 +/- 3.33 mm3) and maximal dimensions (r = 0.99, SEE = 0.16 cm, mean difference = 0.03 +/- 0.16 cm) between phantoms and their corresponding replicas. Visual and tactile examination of mitral valve models by two blinded observers allowed correct depiction of mitral valve anatomy and pathology in all cases. CONCLUSIONS: Stereolithographic modeling of echocardiographic images is feasible and provides tangible polyacrylic models that are true to scale, shape and volume. Such models offer accurate depiction of mitral valve anatomy and pathology in patients studied with transesophageal echocardiography. This technique could have substantial impact on diagnosis, management and preoperative planning in complex cardiovascular disorders.

IV milrinone for cardiac output increase and maintenance: comparison in nonhyperdynamic SIRS/sepsis and congestive heart failure.

OBJECTIVE: To characterize the effect of the phosphodiesterase inhibitor (PDEI) milrinone in adult patients with a non-hyperdynamic condition during the course of the systemic inflammatory response syndrome (SIRS) or sepsis when compared with patients with congestive heart failure (CHF). PDEIs are potent inhibitors of cytokine production and expression. We hypothesized that there might be an outstanding beneficial effect of PDEIs in the setting of SIRS/sepsis. DESIGN: Prospective, open labeled, protocol-driven pilot study. PATIENTS: Nine patients with a nonhyperdynamic hemodynamic condition during SIRS/sepsis (group 1) and seven patients with CHF (group 2) requiring inotropic support. All patients were having heart disease. All patients had a combination of various catecholamines at the time of inclusion in the study and had received fluid resuscitation to an extent that left ventricular stroke work index (LVSWI) did not increase further. INTERVENTION: Milrinone infusion at a rate of 0.5 microg/kg per min in addition to preexisting catecholamine therapy. MEASUREMENTS AND RESULTS: Measurements of cardiac index (CI; thermodilution) and calculation of vascular resistance and LVSWI was done every 8 h for at least 40 h during milrinone infusion. CI and LVSWI significantly increased in both groups (p < 0.001 and p = 0.006, respectively). There were no significant differences between groups in these parameters (p > 0.11 and p > 0.13, respectively). The LVSWI increase occurred while there was a decrease in pulmonary capillary wedge pressure, suggesting a true and comparable improvement in cardiac function relatively independent of loading conditions. Preexisting catecholamines had to be increased in both groups (NS). Milrinone had to be discontinued in one patient due to hypotension. CONCLUSION: Milrinone administration is feasible in selected patients with a non-hyperdynamic condition during SIRS/sepsis and with preexisting heart disease. Under the conditions of this study, milrinone was no better in terms of CI and LVSWI maintenance in septic cardiac dysfunction when compared with CHF. These results do not necessarily extend to other cohorts with no preexisting heart disease.

Guanine-rich (GGNNGG) elements at chromosomal breakpoints interact with a loop-forming, single-stranded DNA-binding protein.

Proto-oncogene-activation is frequently preceded by chromosomal translocations. Several models suggest that DNA single-strands and loops may serve as intermediates in the process of illegitimate recombination. Guanine-rich, repetitive elements are preferred sites of chromosomal exchange and can undergo conformational changes which result in the generation of single-stranded DNA. Here we describe a single-stranded DNA-binding protein which binds specifically to guanine-rich elements at the breakpoints of human reciprocal translocations, including the t(14;18), t(2;8), t(9;22), t(15;17) and t(4;11) in leukemia and lymphoma. The primitive binding consensus consists of two guanine-residues on either side separated by a spacer of at least two nucleotides (GGN-NGG). Binding activity is unaltered by a spacer length of up to 46 nucleotides. These data suggest that the protein has the unique ability to form or stabilize DNA-loops and may thus play a general role in recombination.