Levosimendan in intensive care and emergency medicine: literature update and expert recommendations for optimal efficacy and safety.

The inodilator levosimendan, in clinical use for over two decades, has been the subject of extensive clinical and experimental evaluation in various clinical settings beyond its principal indication in the management of acutely decompensated chronic heart failure. Critical care and emergency medicine applications for levosimendan have included postoperative settings, septic shock, and cardiogenic shock. As the experience in these areas continues to expand, an international task force of experts from 15 countries (Austria, Belgium, China, Croatia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Spain, Sweden, Switzerland, and the USA) reviewed and appraised the latest additions to the database of levosimendan use in critical care, considering all the clinical studies, meta-analyses, and guidelines published from September 2019 to November 2021. Overall, the authors of this opinion paper give levosimendan a "should be considered" recommendation in critical care and emergency medicine settings, with different levels of evidence in postoperative settings, septic shock, weaning from mechanical ventilation, weaning from veno-arterial extracorporeal membrane oxygenation, cardiogenic shock, and Takotsubo syndrome, in all cases when an inodilator is needed to restore acute severely reduced left or right ventricular ejection fraction and overall haemodynamic balance, and also in the presence of renal dysfunction/failure.

Preoperative and perioperative use of levosimendan in cardiac surgery: European expert opinion.

In cardiac surgery, postoperative low cardiac output has been shown to correlate with increased rates of organ failure and mortality. Catecholamines have been the standard therapy for many years, although they carry substantial risk for adverse cardiac and systemic effects, and have been reported to be associated with increased mortality. On the other hand, the calcium sensitiser and potassium channel opener levosimendan has been shown to improve cardiac function with no imbalance in oxygen consumption, and to have protective effects in other organs. Numerous clinical trials have indicated favourable cardiac and non-cardiac effects of preoperative and perioperative administration of levosimendan. A panel of 27 experts from 18 countries has now reviewed the literature on the use of levosimendan in on-pump and off-pump coronary artery bypass grafting and in heart valve surgery. This panel discussed the published evidence in these various settings, and agreed to vote on a set of questions related to the cardioprotective effects of levosimendan when administered preoperatively, with the purpose of reaching a consensus on which patients could benefit from the preoperative use of levosimendan and in which kind of procedures, and at which doses and timing should levosimendan be administered. Here, we present a systematic review of the literature to report on the completed and ongoing studies on levosimendan, including the newly commenced LEVO-CTS phase III study (NCT02025621), and on the consensus reached on the recommendations proposed for the use of preoperative levosimendan.

[Perioperative care of patients with diastolic heart failure. Interface to anesthesia]. / Perioperative Betreuung von Patienten mit diastolischer Herzinsuffizienz. Schnittstelle zur Anästhesie.

Diastolic heart failure leads to an increase in perioperative morbidity and mortality. The prevalence of this disease is rising and multiple risk factors have already been identified. Besides higher age and female gender, arterial hypertension, diabetes mellitus and coronary artery disease in particular have to be considered. Clinical examination and laboratory analyses are important for preoperative evaluation; however, echocardiography plays the most important role in the diagnostics of diastolic heart failure. The transmitral flow profile can be used to differentiate the grades of diastolic dysfunction using the ratio between early passive ventricular filling (E) and late active filling due to atrial contraction (A). Data concerning the ideal anesthesia technique are for the most part lacking; however, the application of thoracic epidural anesthesia seems to be beneficial. A great deal of attention has to be paid to the intraoperative volume status of patients with diastolic dysfunction as hypovolemia and hypervolemia can both have detrimental effects. Arrhythmias and major changes in blood pressure put this special group of patients at additional risks.

Platelet function testing to time surgery in patients on dual antiplatelet therapy?

In patients pretreated with P2Y12 receptor inhibitors who need to undergo non-emergent cardiac or major non-cardiac surgery, current guidelines of the European Society of Cardiology recommend postponing surgery for at least five days after last intake of clopidogrel or ticagrelor, and for seven days after last intake of prasugrel, unless there is high risk of ischemic events. However, a fixed five to seven days preoperative waiting period may be challenged, in the presence of inter-individual variability in on-treatment platelet reactivity. Therefore, Society of Thoracic Surgeons guidelines suggest to base decisions about a surgical delay on platelet function although both, the optimal platelet function assay and a bleeding cutoff have not yet been defined by large scale multicenter trials. This review aims to provide an overview on current knowledge of P2Y12 receptor induced platelet inhibition and surgery related bleeding and the potential role of platelet function analysis to time surgery.

[Peripartum aortic dissection]. / Peripartale Aortendissektion.

A 29-year-old primagravida developed severe chest pains during labor. An emergency caesarean section was performed as the symptoms persisted. Imaging diagnosis immediately after delivery revealed an acute proximal (type A) aortic dissection. The patient was transferred to the nearest cardiothoracic surgery centre and successful emergency surgical aortic repair was performed. The perioperative course of a type A aortic dissection during pregnancy and labor is complicated by time pressure, diagnostic restrictions until delivery and potentially fatal uterine bleeding during cardiopulmonary bypass and hypothermic cardiac arrest. This case report describes the diagnosis and the surgical, anesthesiological and gynecological management of this life-threatening peripartum complication.

[Endocarditis prophylaxis in children and adolescents : implementation of the current guidelines in the Department of Paediatric Surgery at the Medical University Graz]. / Endokarditisprophylaxe bei Kindern und Jugendlichen : Umsetzung der aktuellen Leitlinien an der Universitätsklinik für Kinderchirurgie in Graz.

The timely administration of endocarditis prophylaxis means an additional stress situation for many children and their parents in an already stressful preoperative period. In addition it causes an increased organizational effort most of all in the day care department. Over many decades the use of prophylactic antibiotics to prevent infective endocarditis was recommended in patients with underlying cardiac conditions undergoing medical procedures which could lead to bacteraemia. However, transient bacteraemia occurs commonly during routine daily activities such as cleaning teeth or chewing. Most cases of endocarditis are not related to a medical procedure. There are currently no randomized and carefully controlled human trials to definitely prove the effectiveness and efficiency of endocarditis prophylaxis. Therefore, the new guidelines recommend the use of antibiotic prophylaxis only for cardiac conditions associated with the highest risk of adverse outcome from endocarditis. In paediatric surgery and paediatric anaesthesiology this applies mainly to patients with congenital heart disease. The implementation of the new guidelines in the Department of Paediatric Surgery at the Medical University Graz is illustrated in the following article.

Arterial oxygen tension increase 2-3 h after hyperbaric oxygen therapy: a prospective observational study.

BACKGROUND: Inhalation of hyperbaric oxygen (HBO) has been reported to decrease arterial oxygen tension (PaO(2)) in the early period after exposure. The current investigation aimed at evaluating whether and to what extent arterial blood gases were affected in mechanically ventilated intensive care patients within 6 h after HBO treatment. METHODS: Arterial blood gases were measured in 11 ventilated subjects [nine males, two females, synchronized intermittent mandatory ventilation (SIMV) mode] undergoing HBO therapy for necrotizing soft tissue infection (seven patients), burn injury (two patients), crush injury (one patient) and major abdominal surgery (one patient). Blood gases were obtained with the patients in the supine position under continuous analgesia and sedation before the hyperbaric session (baseline), during isopression, after decompression, after each transport, and 1, 2, 3 and 6 h after exposure. Heart rates and blood pressures were recorded. Intensive care unit (ICU) ventilator settings remained unchanged. Transport and chamber ventilator settings were adjusted to baseline with maintenance of tidal volumes and positive end-expiratory pressure (PEEP) levels. The hyperbaric protocol consisted of 222.9 kPa (2.2 absolute atmospheres) and a 50-min isopression phase. The paired Wilcoxon's test was used. RESULTS: Major findings (median values, 25%/75% quartiles) as per cent change of baseline: PaO(2) values decreased by 19.7% (7.0/31.7, P < 0.01) after 1 h and were elevated over baseline by 9.3% (1.5/13.7, P < 0.05) after 3 h. SaO(2), alveolar-arterial oxygen tension difference and PaO(2)/FiO(2) ratio behaved concomitantly. Acid-base status and carbon dioxide tension were unaffected. CONCLUSION: Arterial oxygen tension declines transiently after HBO and subsequently improves over baseline in intensive care patients on volume-controlled mechanical ventilation. The effectiveness of other ventilation modes or a standardized recruitment manoeuvre has yet to be evaluated.

Beneficial outcome after prostaglandin-induced post-partum cardiac arrest using levosimendan and extracorporeal membrane oxygenation.

BACKGROUND: Administration of high doses of prostaglandins is a frequently performed and effective method for the treatment of atonic uterine haemorrhage in order to increase uterine muscle tone. Rarely, however, these drugs may cause life-threatening complications including bronchospasm, acute pulmonary oedema and myocardial infarction caused by coronary spasms. METHODS: We discuss the management of a patient suffering post-partum atonic uterine bleeding, catecholamine-resistant cardiac arrest and fulminant pulmonary failure due to deleterious side-effects of treatment with prostaglandins. RESULTS: During therapy resistant cardiopulmonary resuscitation, the addition of levosimendan to standard medications resulted in a prompt stabilization of haemodynamics. Subsequent treatment of pulmonary failure was successfully managed with ECMO. CONCLUSION: Although levosimendan is not approved for pharmacological treatment of cardiopulmonary arrest, the beneficial effects in this patient suggest an important role of calcium sensitization and vasodilation during prostaglandin-induced cardiac arrest.

Different effects of abciximab and cytochalasin D on clot strength in thrombelastography.

Maximum amplitude (MA) in thrombelastography (TEG) consists of a plasmatic and a platelet component. To assess the magnitude of the plasmatic component, pharmacological approaches have been proposed to eliminate the platelet component. We evaluated the individual and combined effects of abciximab and cytochalasin D on the MA of TEG. Whole blood, platelet-rich plasma (PRP) and homologous platelet-poor plasma (PPP) from 20 healthy volunteers were spiked with abciximab or cytochalasin D or a combination of both and TEGs performed. Abciximab and cytochalasin D decreased MA in all samples. MA of whole blood (18.6 +/- 3.1 mm) and PRP (33.7 +/- 3.5 mm) spiked with abciximab or cytochalasin D alone (15.0 +/- 2.9 mm and 25.0 +/- 4.0 mm) were significantly higher when compared with abciximab and cytochalasin D combined (10.4 +/- 3.0 and 20.2 +/- 3.5 mm). While MA of PRP and homologous PPP were significantly (P < 0.001) different after individual administration of abciximab and cytochalasin D, combination of both abolished this difference (20.2 +/- 3.5 mm and 20.4 +/- 3.7 mm, P = 0.372). In whole blood of critically ill patients or patients undergoing major surgery there was also a significant difference of MA between abciximab alone and in combination with cytochalasin D (16.5 +/- 11.3 mm and 11.3 +/- 7.7 mm, P < 0.001). This indicates that in contrast to individual administration of abciximab or cytochalasin D, a combination of both compounds eliminates the platelet-specific effect on MA of TEG tracings.

Zooxanthellae of the Montastraea annularis species complex: patterns of distribution of four taxa of Symbiodinium on different reefs and across depths.

Corals of the Montastraea annularis complex host several different dinoflagellates in the genus Symbiodinium. Here we address two questions arising from our previous studies of these associations on an offshore reef. First, do the same taxa and patterns of association (Symbiodinium A and B found in higher irradiance habitats than Symbiodinium C) occur on an inshore reef? Second, does M. franksi at the limits of its depth range host only Symbiodinium C, as it does at intermediate depths? In both surveys, a new Symbiodinium taxon and different patterns of distribution (assayed by analyses of small ribosomal subunit RNA genes [srDNA]) were observed. Inshore, a taxon we name Symbiodinium E predominated in higher irradiance habitats in M. franksi and its two sibling species; the only other zooxanthella observed was Symbiodinium C. Offshore, M. franksi mainly hosted Symbiodinium C, but hosted Symbiodinium A, B, C, and E in shallow water and Symbiodinium E and C in very deep water. Symbiodinium E may be stress-tolerant. Observed srDNA heterogeneity within samples of Symbiodinium B, C, and E is interpreted as variation across copies within this multigene family. Experimental bleaching of Symbiodinium C supported this interpretation. Thus sequences from natural samples should be interpreted cautiously.

Repopulation of Zooxanthellae in the Caribbean corals Montastraea annularis and M. faveolata following experimental and disease-associated bleaching.

Caribbean corals of the Montastraea annularis species complex associate with four taxa of symbiotic dinoflagellates (zooxanthellae; genus Symbiodinium) in ecologically predictable patterns. To investigate the resilience of these host-zooxanthella associations, we conducted field experiments in which we experimentally reduced the numbers of zooxanthellae (by transplanting to shallow water or by shading) and then allowed treated corals to recover. When depletion was not extreme, recovering corals generally contained the same types of zooxanthellae as they did prior to treatment. After severe depletion, however, recovering corals were always repopulated by zooxanthellae atypical for their habitat (and in some cases atypical for the coral species). These unusual zooxanthellar associations were often (but not always) established in experimentally bleached tissues even when adjacent tissues were untreated. Atypical zooxanthellae were also observed in bleached tissues of unmanipulated Montastraea with yellow-blotch disease. In colonies where unusual associations were established, the original taxa of zooxanthellae were not detected even 9 months after the end of treatment. These observations suggest that zooxanthellae in Montastraea range from fugitive opportunists and stress-tolerant generalists (Symbiodinium A and E) to narrowly adapted specialists (Symbiodinium B and C), and may undergo succession.

Hyperglycemia reduces coronary collateral blood flow through a nitric oxide-mediated mechanism.

We tested the hypothesis that hyperglycemia alters retrograde coronary collateral blood flow by a nitric oxide-mediated mechanism in a canine Ameriod constrictor model of enhanced collateral development. Administration of 15% dextrose to increase blood glucose concentration to 400 or 600 mg/dl decreased retrograde blood flow through the left anterior descending coronary artery to 78 +/- 9 and 82 +/- 8% of baseline values, respectively. In contrast, saline or L-arginine (400 mg x kg(-1) x h(-1)) had no effect on retrograde flow. Coronary hypoperfusion and 1 h of reperfusion decreased retrograde blood flow similarly in saline- or L-arginine-treated dogs (76 +/- 11 and 89 +/- 4% of baseline, respectively), but these decreases were more pronounced in hyperglycemic dogs (47 +/- 10%). L-arginine prevented decreases in retrograde coronary collateral blood flow during hyperglycemia (100 +/- 5 and 95 +/- 6% of baseline at blood glucose concentrations of 400 and 600 mg/dl, respectively) and after coronary hypoperfusion and reperfusion (84 +/- 14%). The results suggest that hyperglycemia decreases retrograde coronary collateral blood flow by adversely affecting nitric oxide availability.

Diabetes and hyperglycemia impair activation of mitochondrial K(ATP) channels.

Hyperglycemia is an important predictor of cardiovascular mortality in patients with diabetes. We investigated the hypothesis that diabetes or acute hyperglycemia attenuates the reduction of myocardial infarct size produced by activation of mitochondrial ATP-regulated potassium (K(ATP)) channels. Acutely instrumented barbiturate-anesthetized dogs were subjected to a 60-min period of coronary artery occlusion and 3 h of reperfusion. Myocardial infarct size (triphenyltetrazolium chloride staining) was 25 +/- 1, 28 +/- 3, and 25 +/- 1% of the area at risk (AAR) for infarction in control, diabetic (3 wk after streptozotocin-alloxan), and hyperglycemic (15% intravenous dextrose) dogs, respectively. Diazoxide (2.5 mg/kg iv) significantly decreased infarct size (10 +/- 1% of AAR, P < 0.05) but did not produce protection in the presence of diabetes (28 +/- 5%) or moderate hyperglycemia (blood glucose 310 +/- 10 mg/dl; 23 +/- 2%). The dose of diazoxide and the degree of hyperglycemia were interactive. Profound (blood glucose 574 +/- 23 mg/dl) but not moderate hyperglycemia blocked the effects of high-dose (5.0 mg/kg) diazoxide [26 +/- 3, 15 +/- 3 (P < 0.05), and 11 +/- 2% (P < 0.05), respectively]. There were no differences in systemic hemodynamics, AAR, or coronary collateral blood flow (by radioactive microspheres) between groups. The results indicate that diabetes or hyperglycemia impairs activation of mitochondrial K(ATP) channels.

Ethanol enhances the functional recovery of stunned myocardium independent of K(ATP) channels in dogs.

Chronic, intermittent exposure to small amounts of ethanol reduces myocardial infarct size in vivo. We tested the hypothesis that acute administration of ethanol enhances the functional recovery of stunned myocardium and that adenosine triphosphate-dependent potassium (K(ATP)) channels mediate this beneficial effect. Barbiturate-anesthetized dogs were instrumented for measurement of aortic and left ventricular pressure, +dP/dt(max), and subendocardial segment shortening (%SS) and were subjected to five 5-min periods of coronary artery occlusion, each separated by 5 min of reperfusion followed by a 3-h final reperfusion. In four groups (n = 7 each), dogs received 0.9% saline or ethanol (0.25, 0.5, or 1.0 g/kg over 30 min) in a random manner before occlusions and reperfusions. In other groups (n = 7 each), dogs received the K(ATP) channel antagonist glyburide (0.3 mg/kg, IV) 30 min before saline or ethanol (0.25 g/kg) was administered. Dogs receiving saline or glyburide alone demonstrated poor recovery of contractile function during reperfusion (%SS = 0.9% +/- 2.0% and 1.6% +/- 1.2% at 3 h, respectively). Recovery of %SS was enhanced in dogs receiving the 0.25- and 0.5-g/kg doses of ethanol (10.0% +/- 1.8% and 8.6% +/- 2.2% at 3 h, respectively) independent of alterations in hemodynamics or coronary collateral blood flow (radioactive microspheres). Glyburide did not affect improvement of recovery of stunned myocardium produced by ethanol (11.8% +/- 2.2% at 3 h). The results indicate that ethanol enhances the functional recovery of stunned myocardium independent of K(ATP) channels in vivo.

K(ATP) channels mediate the beneficial effects of chronic ethanol ingestion.

Chronic ingestion of low doses of ethanol protects the myocardium from ischemic injury by activating adenosine receptors and protein kinase C. We tested the hypothesis that ATP-dependent potassium (K(ATP)) channels mediate these beneficial effects. Dogs were fed with ethanol (1.5 g/kg) or water mixed with dry food twice per day for 12 wk. After they were acutely instrumented for measurement of hemodynamics, dogs received saline (vehicle) or glyburide (0.1 mg/kg iv) and were subjected to 60 min of coronary artery occlusion followed by 3 h of reperfusion. Infarct size (through triphenyltetrazolium chloride staining) was significantly (P < 0.05) reduced to 14 +/- 1% of the left ventricular area at risk in ethanol-pretreated dogs compared with controls (25 +/- 2%). Glyburide alone did not affect infarct size (25 +/- 3%) but abolished the protective effects of ethanol pretreatment (28 +/- 3%). No differences in hemodynamics or coronary collateral blood flow (through radioactive microspheres) were observed among groups. The results indicate that K(ATP) channels mediate the protective effects of chronic consumption of ethanol.

Low potential of dobutamine and dopexamine to block intestinal peristalsis as compared with other catecholamines.

OBJECTIVE: Catecholamines are frequently used in critically ill patients to restore stable hemodynamics and to improve organ perfusion. One effect of short-term or long-term administration of catecholamines may be inhibition of propulsive motility in the intestine. We therefore analyzed the effect of dopexamine, dobutamine, and dopamine on ileal peristalsis and compared their action with that of epinephrine and norepinephrine, which have long been known to suppress intestinal peristalsis. DESIGN: In vitro study on excised guinea pig ileum segments. SETTING: Laboratory for experimental studies at the University. SUBJECTS: Isolated guinea pig ileum. INTERVENTIONS: Segments of ileum excised from guinea pigs were mounted in a tissue bath in Krebs-Henseleit solution and bubbled with 95% oxygen/5% CO2. Luminal perfusion with the same solution was performed at a rate of 0.35 mL/min. The bath temperature was kept at 36.5 degrees C. Peristalsis was recorded via changes in the intraluminal pressure. The drugs under investigation (dopamine, epinephrine, norepinephrine, dobutamine, and dopexamine) were added to the tissue bath. MEASUREMENTS AND MAIN RESULTS: Low concentrations of each catecholamine, except epinephrine, caused a decrease in the pressure threshold, which reflects a stimulatory effect on peristalsis. Higher catecholamine concentrations caused a concentration-related increase in the threshold, cumulating in a complete block of peristalsis. The rank order of inhibitory potency was epinephrine > norepinephrine > dopamine > dobutamine approximately dopexamine. Dobutamine and dopexamine were about 500-fold less active than epinephrine in suppressing peristalsis. CONCLUSIONS: This study shows that dobutamine and dopexamine have the least potential to block propulsive motility in the intestine, whereas epinephrine demonstrates the most adverse inhibitory effect. Because at low concentrations dobutamine and dopexamine even stimulate peristalsis, these drugs appear to be superior compared with other catecholamines with regard to their direct effects on intestinal motility.

Sarcolemmal and mitochondrial adenosine triphosphate- dependent potassium channels: mechanism of desflurane-induced cardioprotection.

BACKGROUND: Volatile anesthetic-induced preconditioning is mediated by adenosine triphosphate-dependent potassium (KATP) channels; however, the subcellular location of these channels is unknown. The authors tested the hypothesis that desflurane reduces experimental myocardial infarct size by activation of specific sarcolemmal and mitochondrial KATP channels. METHODS: Barbiturate-anesthetized dogs (n = 88) were acutely instrumented for measurement of aortic and left ventricular pressures. All dogs were subjected to a 60-min left anterior descending coronary artery occlusion followed by 3-h reperfusion. In four separate groups, dogs received vehicle (0.9% saline) or the nonselective KATP channel antagonist glyburide (0.1 mg/kg intravenously) in the presence or absence of 1 minimum alveolar concentration desflurane. In four additional groups, dogs received 45-min intracoronary infusions of the selective sarcolemmal (HMR 1098; 1 microg. kg-1. min-1) or mitochondrial (5-hydroxydecanoate [5-HD]; 150 microg. kg-1. min-1) KATP channel antagonists in the presence or absence of desflurane. Myocardial perfusion and infarct size were measured with radioactive microspheres and triphenyltetrazolium staining, respectively. RESULTS: Desflurane significantly (P < 0.05) decreased infarct size to 10 +/- 2% (mean +/- SEM) of the area at risk as compared with control experiments (25 +/- 3% of area at risk). This beneficial effect of desflurane was abolished by glyburide (25 +/- 2% of area at risk). Glyburide (24 +/- 2%), HMR 1098 (21 +/- 4%), and 5-HD (24 +/- 2% of area at risk) alone had no effects on myocardial infarct size. HMR 1098 and 5-HD abolished the protective effects of desflurane (19 +/- 3% and 22 +/- 2% of area at risk, respectively). CONCLUSION: Desflurane reduces myocardial infarct size in vivo, and the results further suggest that both sarcolemmal and mitochondrial KATP channels could be involved.

Diabetes abolishes ischemic preconditioning: role of glucose, insulin, and osmolality.

Recent evidence indicates that hyperglycemia is an important risk factor for the development of cardiovascular disease. We tested the hypothesis that myocardial infarct size is related to blood glucose concentration in the presence or absence of ischemic preconditioning (PC) stimuli in canine models of diabetes mellitus and acute hyperglycemia. Barbiturate-anesthetized dogs were subjected to a 60-min period of coronary artery occlusion and 3-h reperfusion. Infarct size was 24 +/- 2% of the area at risk (AAR) for infarction in control dogs. PC significantly (P < 0.05) decreased the extent of infarction in normal (8 +/- 2% of AAR), but not diabetic (22 +/- 4% of AAR), dogs. Infarct size was linearly related to blood glucose concentration during acute hyperglycemia (r = 0.96; P < 0.001) and during diabetes (r = 0.74; P < 0.002) in the presence or absence of PC stimuli. Increases in serum osmolality caused by administration of raffinose (300 g) did not increase infarct size (11 +/- 3% of AAR) or interfere with the ability of PC to protect against infarction (2 +/- 1% of AAR). The results indicate that hyperglycemia is a major determinant of the extent of myocardial infarction in the dog.