Karl Werdan

Communication of end-of-life decisions in European intensive care units.

ObjectiveTo examine end-of-life (EOL) practices in European ICUs: who makes these decisions, how they are made, communication of these decisions and questions on communication between the physicians, nurses, patients and families.DesignData collected prospectively on EOL decisions facilitated by a questionnaire including EOL decision categories, geographical regions, mental competency, information about patient wishes, and discussions with patients, families and health care professionals.Setting37 European ICUs in 17 countriesPatientsICU physicians collected data on 4,248 patients.Results95% of patients lacked decision making capacity at the time of EOL decision and patient’s wishes were known in only 20% of cases. EOL decisions were discussed with the family in 68% of cases. Physicians reported having more information about patients’ wishes and discussions in the northern countries (31%, 88%) than central (16%, 70%) or southern (13%, 48%) countries. The family was more often told (88%) than asked (38%) about EOL decisions. Physicians’ reasons for not discussing EOL care with the family included the fact that the patient was unresponsive to therapy (39%), the family was unavailable (28%), and the family was thought not to understand (25%).ConclusionsICU patients typically lack decision-making capacity, and physicians know patients’ wishes in only 20% of EOL decisions. There were regional differences in discussions of EOL decisions with families and other physicians. In European ICUs there seems to be a need to improve communication

Impaired regulation of cardiac function in sepsis, SIRS, and MODS.

In sepsis, systemic inflammatory response syndrome (SIRS), and multiorgan dysfunction syndrome (MODS), a severe prognostically relevant cardiac autonomic dysfunction exists, as manifested by a strong attenuation of sympathetically and vagally mediated heart rate variability (HRV). The mechanisms underlying this attenuation are not limited to the nervous system. They also include alterations of the cardiac pacemaker cells on a cellular level. As shown in human atrial cardiomyocytes, endotoxin interacts with cardiac hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels, which mediate the pacemaker current If and play an important role in transmitting sympathetic and vagal signals on heart rate and HRV. Moreover, endotoxin sensitizes cardiac HCN channels to sympathetic signals. These findings identify endotoxin as a pertinent modulator of the autonomic nervous regulation of heart function. In MODS, the vagal pathway of the autonomic nervous system is particularly compromised, leading to an attenuation of the cholinergic antiinflammatory reflex. An amelioration of the blunted vagal activity appears to be a promising novel therapeutic target to achieve a suppression of the inflammatory state and thereby an improvement of prognosis in MODS patients. Preliminary data revealed therapeutic benefits (increased survival rates and improvements of the depressed vagal activity) of the administration of statins, beta-blockers, and angiotensin-converting enzyme inhibitors in patients with MODS.

A post-receptor defect of adenylyl cyclase in severely failing myocardium from children with congenital heart disease.

The aim of this study was to determine whether a defect at the post-receptor level of adenylyl cyclase may also contribute to the decreased effectiveness of cAMP-increasing agents in severely failing patients with congenital heart disease. The severity of congestive heart failure in 31 patients with congenital heart disease was graded by a scoring system which included a description of historical and clinical variables. Patients were divided into a group with no or mild heart failure (score < or = 6) and a group with severe heart failure (score > 6). beta-Adrenoceptor-stimulated adenylyl cyclase activity was significantly decreased by 65% in patients with severe heart failure in comparison to the group of patients with no or mild heart failure. In addition, receptor-independent adenylyl cyclase stimulation by forskolin was reduced by 52% in patients with score > 6 compared to patients with score < or = 6. This post-receptor defect of adenylyl cyclase was apparently due to a decrease in the activity of catalytic subunit of adenylyl cyclase as adenylyl cyclase stimulation by forskolin in the presence of Mn2+ which uncouples catalytic subunit from the G proteins, G(s) and G(i), was also significantly diminished in the patients with severe heart failure. In contrast, the level of inhibitory G protein alpha-subunits was apparently not different in the two groups. In summary, the data indicate that a defect at the catalytic subunit of adenylyl cyclase apparently contributes to the decreased effectiveness of cAMP-increasing agents in severely failing patients with congenital heart disease.

Der anaphylaktische Schock

EinleitungDas Spektrum akut lebensbedrohlicher anaphylaktischer/anaphylaktoider Reaktionen in der Anaesthesiologie ist Gegenstand dieser Übersicht, ebenso präoperative Präventivmaßnahmen bei Allergie-Patienten und die Prävention und Therapie des anaphylaktischen Schocks. Unbehandelt geht die Anaphylaxie mit einer erheblichen Morbidität (Schock, Multiorganversagen) und Letalität einher und kann innerhalb weniger Minuten im exitus letalis enden. Schwere anaphylaktische Reaktionen können selbst unter adäquater Therapie progredient verlaufen, und es kann nach einer vorübergehenden Besserung zu einem erneuten Ausbruch der Symptomatik kommen. Nach den Sofortmaßnahmen erfolgen Überwachung und Behandlung des Patienten mit anaphylaktischem Schock auf der Intensivstation.

EXPOSURE TO THE N-3 POLYUNSATURATED FATTY ACID DOCOSAHEXAENOIC ACID IMPAIRS ALPHA 1-ADRENOCEPTOR-MEDIATED CONTRACTILE RESPONSES AND INOSITOL PHOSPHATE FORMATION IN RAT CARDIOMYOCYTES

The beneficial effects of n-3 polyunsaturated fatty acids of fish oil in the prevention of fatal arrhythmias in myocardial ischemia were suggested to be at least in part mediated by a modulation of dihydropyridine-sensitive L-type calcium channels. As cardiac α1-adrenoceptor stimulation has been suggested to have no significant effect on L-type calcium channels, the aim of this study using cultured neonatal rat cardiomyocytes was to investigate whether chronic n-3 polyunsaturated fatty acid exposure may have an influence on α1-adrenoceptor-induced positive inotropic effects and induction of arrhythmias. Pretreatment of the rat cardiomyocytes for 3 days in the presence of the n-3 polyunsaturated fish oil-derived fatty acid docosahexaenoic acid (60 μmol/l) markedly decreased α1-adrenoceptor-stimulated increase in contraction velocity and induction of arrhythmias. The increase in contraction velocity of the cardiomyocytes induced by the β-adrenoceptor agonist isoprenaline was also markedly reduced by the n-3 fatty acid pretreatment. Basal contractile amplitude and spontaneous beating frequency of the cardiomyocytes were not significantly altered by the docosahexaenoic acid exposure. The pretreatment of the rat cardiomyocytes for 3 days in the presence of docosahexaenoic acid (60 μmol/l) decreased α1-adrenoceptor-stimulated formation of the calcium-mobilizing second messenger IP3 and its metabolites IP2 and IP1 by 55%. The depression of IP3 formation by docosahexaenoic acid treatment was not mediated by a decreased uptake of myo-inositol into the cardiomyocytes nor by a decreased synthesis of phosphatidylinositol bisphosphate (PIP2), the substrate of phospholipase C. The level of glycerol-3-phosphate, an important substrate of the phosphoinositide cycle, was unaltered by the docosahexaenoic acid pretreatment. Receptor binding studies revealed that the dissociation constant and maximal binding capacity of the α1-adrenoceptor antagonist (3H)prazosin was unchanged by the n-3 polyunsaturated fatty acid exposure. β-Adrenoceptor-and forskolin-stimulated adenylyl cyclase activities were not diminished by the docosahexaenoic acid pretreatment. Chronic exposure of the cardiomyocytes to the n-6 polyunsaturated fatty acid arachidonic acid (60 μmol/l) did neither significantly alter α1-adrenoceptor-induced inositol phosphate formation nor α1-adrenoceptor-stimulated increase in contraction velocity. The results presented show that chronic n-3 polyunsaturated fatty acid pretreatment of rat cardiomyocytes leads to a marked impairment of α1-adrenoceptor-induced positive inotropic effects and induction of arrhythmias concomitant with a n-3 fatty acid-induced decrease in IP3 formation. This derangement of the phosphonositide pathway by chronic n-3 fatty acid exposure may, thus, contribute to the beneficial effects of fish oil-derived fatty acids in the prevention of fatal arrhythmias in myocardial ischemia.

Endogenous ADP-ribosylation of elongation factor-2 by interleukin-1β

Eukaryotic elongation factor-2 (eEF-2) catalyses the motion of the growing peptide chain relative to the mRNA at the ribosomes during protein synthesis. This highly conserved G-protein is the specific target of two lethal bacterial toxins, Pseudomonas aeruginosa exotoxin A and diphtheria toxin. These toxins exert their detrimental action by ADP-ribosylating a biologically unique posttranslationally modified histidine residue (diphthamide715) within eEF-2, thus inactivating the enzyme. Diphthamide715 is also the target of endogenous (mono) ADP-ribosyl transferase activity. In this article, we report the first known activator of endogenous ADP-ribosylation of eEF-2, interleukin-1β (IL-1β). Thereby, systemic inflammatory processes may link to protein synthesis regulation.

Zytokine und Herzkrankheiten

UNLABELLEDnAcute septic cardiomyopathy is-to our present knowledge-the heart disease most strongly interrelated with cytokines. Myocardial depression by cytokines is characterized by their pleiotropic actions mediating not only impairment of one, but several inotropic cascades. Information concerning the relevance of cytokines in non-septic heart diseases is-at present-scarce: Concepts emerge in cases of myocarditis, heart failure and cardiomyopathies, acute coronary syndromes, systemic inflammatory response due to cardiopulmonary bypass, heart transplant rejection and Kawasaki disease.nnnCONCLUSIONnCytokines are involved in heart diseases.ZusammenfassungDie akute septische Kardiomyopathie ist nach derzeitigem Kenntnisstand die am meisten von Zytokinwirkungen geprägte Herzerkrankung. Die zeitlich verzögert einsetzende Myokarddepression durch Zytokine erfolgt nicht über eine einzelne inotrope Signalkette, sondern pleiotrop. Informationen zur Relevanz von Zytokinen bei nicht-septischen Herzerkrankungen sind noch spärlich: Erste Konzepte zeichnen sich ab bei der Myokarditis, der Herzinsuffizienz und den Kardiomyopathien, den akuten Koronarsyndromen, der systemischen Entzündungsreaktion nach Herzoperationen mit kardiopulmonalem Bypass, der Abstoßungsreaktion nach Herztransplantation und der Kawasaki-Erkrankung.□ SchlußfolgerungZytokine sind für die Entstehung und den Verlauf von Herzkrankheiten bedeutungsvoll.SummaryAcute septic cardiomyopathy is — to our present knowledge — the heart disease most strongly interrelated with cytokines. Myocardial depression by cytokines is characterized by their pleiotropic actions mediating not only impairment of one, but several inotropic cascades. Information concerning the relevance of cytokines in non-septic heart diseases is — at present — scarce: Concepts emerge in cases of myocarditis, heart failure and cardiomyopathies, acute coronary syndromes, systemic inflammatory response due to cardiopulmonary bypass, heart transplant rejection and Kawasaki disease.□ ConclusionCytokines are involved in heart diseases.

β-Adrenoceptor desensitization despite cardiac denervation in human failing transplanted myocardium

The aim of this study, using right ventricular endomyocardial biopsies, was to determine whether adenylyl cyclase activity is decreased-despite cardiac denervation-in human failing transplanted myocardium. beta-Adrenoceptor-stimulated adenylyl cyclase activity in membranes of moderately failing transplanted hearts was significantly decreased by 49% in comparison to non-failing transplanted hearts. Receptor-independent adenylyl cyclase stimulation (forskolin + GTP, forskolin + Mn2+) and the level of inhibitory G protein alpha-subunits were not significantly different in membranes of failing vs. non-failing transplanted myocardium. The results indicate that similar to failing non-transplanted myocardium the responsiveness to beta-adrenoceptor agonists is also decreased in failing transplanted myocardium.

The impact of insulin-like growth factor-1 on the pattern of cardiac elongation factor-2 variants in a model of overload.

Because of its key role in proteosynthesis, the total content of elongation factor-2 (EF-2) and the distribution of six main EF-2 variants were investigated after Pseudomonas Exotoxin A catalyzed [32P]ADP-ribosylation using 1D-PAGE and isoelectric focusing (IEF) in a rat model of hemodynamic overload with variable degrees of cardiac hypertrophy: Chronic NO-synthase inhibition by L-NAME (N-omega-nitro-L-arginine-methyl-esther; 0.75 mg/ml drinking water) induced arterial hypertension without hypertrophy but myocardial apoptosis; additional treatment with IGF-1 (osmotic micropumps) did not modify hypertension but reduced apoptosis allowing moderate hypertrophy of the left ventricles. Total EF-2 did not significantly increase in rats with hemodynamic overload with or without IGF-1 supplementation. A positive correlation was found between an acidic EF-2 variant and apoptosis (p = 0.01). Hypertrophy under additional IGF-1 was combined with a shift of the EF-2 variants to basic subtypes (p < 0.01). This finding may be indicative of the trophic potency of IGF-1.

Role of Cytokines in Septic Cardiomyopathy

The interrelations of cytokine and nitric oxide (NO) metabolism with heart function have been best documented for the heart in sepsis. The existence of human septic myocardial depression in intensive care patients was only unequivocally proved in the 1980s by the group of Parrillo, utilizing a nuclear imaging technique. Septic cardiomyopathy is frequently masked by a seemingly normal cardiac output. However, relative to the lowered systemic vascular resistance in sepsis, resulting in a reduced afterload, cardiac outputs and ventricular ejection fractions of septic patients are often not adequately enhanced. Septic cardiomyopathy involves both the right and the left ventricle; global as well as regional contractile disturbances occur and systolic pump as well as diastolic relaxation failure. Septic cardiomyopathy is potentially reversible. In response to volume substitution, the hearts can be considerably enlarged. The disease is not primarily hypoxic in nature, as coronary sinus blood flow is high and as coronary vessels are dilated. Difficult situations may arise, when septic cardiomyopathy develops in patients with pre-existing coronary heart disease. The severity of myocardial depression correlates with a poor prognosis, heart failure accounting for about 10% of fatalities from sepsis and septic shock. Septic cardiomyopathy is prevalent in Gram-positive, Gram-negative, fungal and viral sepsis, and left ventricular stroke work indices are compromised to a similar degree independent of the causative germ, pointing at the relevance of the final mediator pathways as opposed to the specific virulence factors.