Sonja Fruhwald

Levosimendan : molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan

The molecular background of the Ca(2+)-sensitizing effect of levosimendan relates to its specific interaction with the Ca(2+)-sensor troponin C molecule in the cardiac myofilaments. Over the years, significant preclinical and clinical evidence has accumulated and revealed a variety of beneficial pleiotropic effects of levosimendan and of its long-lived metabolite, OR-1896. First of all, activation of ATP-sensitive sarcolemmal K(+) channels of smooth muscle cells appears as a powerful vasodilator mechanism. Additionally, activation of ATP-sensitive K(+) channels in the mitochondria potentially extends the range of cellular actions towards the modulation of mitochondrial ATP production and implicates a pharmacological mechanism for cardioprotection. Finally, it has become evident, that levosimendan possesses an isoform-selective phosphodiesterase-inhibitory effect. Interpretation of the complex mechanism of levosimendan action requires that all potential pharmacological interactions are analyzed carefully in the framework of the currently available evidence. These data indicate that the cardiovascular effects of levosimendan are exerted via more than an isolated drug-receptor interaction, and involve favorable energetic and neurohormonal changes that are unique in comparison to other types of inodilators.

Intestinal motility disturbances in intensive care patients pathogenesis and clinical impact

BackgroundGastrointestinal motility disturbances in critically ill patients are frequent in the ICU setting, causing considerable discomfort and are associated with increased rates of morbidity and mortality. This review focuses on the pathophysiological basis of intestinal motility, the major patterns of pathological motility alterations, the impact on patient outcome, and current therapeutic options.DiscussionIntestinal motility is controlled by the enteric nervous system, modulated by hormones and extrinsic afferent and efferent neurons. Pathological motility disturbances can affect the stomach, small bowel, and colon separately or in combination. Changes in esophageal motor activity contribute to the aspiration of gastric juice, whereas early enteral feeding most frequently fails due to gastric intolerance. Disturbances in digestive and interdigestive motility patterns and the inability to switch motor activity from the interdigestive to the digestive pattern also contribute to feeding disability and thus to increased morbidity and mortality as well.ConclusionsThe therapeutic options for motility disturbances in critically ill patients include the adjustment of electrolyte imbalances, tailored fluid management, early enteral feeding, appropriate management of catecholamines and drugs used for analgosedation, and prokinetic drugs. Unfortunately, the therapeutic options for treating motility disturbances in ICU patients are still limited. This situation requires careful assessment of ICU patients with respect to gut motility disturbances and their pathophysiological mechanisms and an individually tailored treatment to prevent further aggravation of existing motility disturbances.

Gastrointestinal motility in acute illness

ZusammenfassungKritisch kranke Patienten leiden häufig unter Störungen der Darmmotilität, einerseits als Folge der primären Erkrankung, welche die Aufnahme auf eine Intensivstation notwendig macht, andererseits als Komplikation des Intensivaufenthaltes. Störungen der Darmmotilität können durch Beeinträchtigungen der muskulären Funktion des Gastrointestinaltraktes, der Schrittmacherzellen des Darmes oder der nervalen Aktivität ausgelöst werden. Das enterale Nervensystem als neuronales Kontrollsystem des Darmes, enthält die größte Ansammlung von Nervenzellen (108 Zellen) außerhalb des zentralen Nervensystems. Das enterische Nervensystem funktioniert unabhängig vom zentralen Nervensystem und generiert nach Bedarf verschiedenste Motilitätsmuster: Die postprandiale Motilität beginnt nach der Nahrungsaufnahme, die interdigestive Motilität startet einige Stunden nach dem Essen. Wichtig für eine ungestörte Motilität ist die balancierte Interaktion zwischen hemmenden und stimulierenden Einflüssen. Kommt dieses Gleichgewicht aus dem Lot, sind schwere Darmmotilitätsstörungen, welche sich nach ihrem klinischen Erscheinungsbild und ihrer Ausbreitung unterscheiden, die Folge. Diese Übersichtsarbeit befasst sich mit dem Erscheinungsbild spezieller Motilitätsstörungen (Gastroparese, Postoperativer Ileus und Ogilvie Syndrom) sowie mit allgemeinen und speziellen Therapieoptionen, um die Häufigkeit oder den Schweregrad dieser Motilitätsstörungen zu reduzieren.SummaryCritical illness affects gastrointestinal motility – not only as a primary problem, which brings the patient to the intensive care unit (ICU), but also as a complication consecutive to the ICU stay. Motility disturbances may result from impaired function of gastrointestinal muscle, pacemaker cell function and nerve activity. The most important neural control system is the enteric nervous system that contains the largest collection of neurons (108 cells) outside the central nervous system. Through its organization it can operate independently of the brain and generate motility patterns according to need: a postprandial motility pattern starting after food intake, and an interdigestive motility pattern starting several hours after a meal. Undisturbed intestinal motility depends critically on a balanced interaction between inhibition and excitation, and a disturbance in this balance leads to severe derangements of intestinal motility. These motility disturbances differ in clinical appearance and location but can affect all parts of the gastrointestinal tract. This review focuses on select motility disturbances such as gastroparesis, postoperative ileus, and Ogilvies syndrome. Generally effective methods to treat these conditions are given. Finally, we focus on special management options to prevent such motility disturbances or to reduce their severity.

Potential Factors for Inadequate Voriconazole Plasma Concentrations in Intensive Care Unit Patients and Patients with Hematological Malignancies

ABSTRACT Voriconazole plasma concentrations (VPCs) vary widely, and concentrations outside the therapeutic range are associated with either worse outcome in invasive aspergillosis (IA) or increased toxicity. The primary goal of this cohort study conducted in a real-life setting was to identify potential factors associated with inadequate VPCs in ICU patients and patients with hematological malignancies. Within a period of 12 months, trough VPCs were obtained and analyzed with high-performance liquid chromatography, and the adequate range was defined as 1.5 to 5.5 mg/liter. VPCs of <1.5 mg/liter were defined as low, whereas VPCs of >5.5 mg/liter were defined as potentially toxic. A total of 221 trough VPCs were obtained in 61 patients receiving voriconazole, and 124/221 VPCs (56%) were found to be low. Multivariate analysis revealed that low VPCs were significantly associated with clinical failure of voriconazole, prophylactic use, younger age, underlying hematological malignancy, concomitant proton pump inhibitor (PPI) (pantoprazole was used in 88% of the patients), and absence of side effects. Low VPCs remained an independent predictor of clinical failure of voriconazole. The defined adequate range was reached in 79/221 (36%) VPCs. In 18 samples (8%), potentially toxic levels were measured. Multivariate analysis revealed higher body mass index (BMI), absence of hematological malignancy, therapeutic application, and diarrhea as factors associated with potentially toxic VPCs. Neurotoxic adverse events occurred in six patients and were mostly associated with VPCs in the upper quartile of our defined adequate range. In conclusion, potential factors like younger age, prophylaxis, underlying hematological malignancy, BMI, and concomitant PPI should be considered within the algorithm of voriconazole treatment.

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

ObjectiveCatecholamines 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. DesignIn vitro study on excised guinea pig ileum segments. SettingLaboratory for experimental studies at the University. SubjectsIsolated guinea pig ileum. InterventionsSegments 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°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 ResultsLow 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 ∼ dopexamine. Dobutamine and dopexamine were about 500-fold less active than epinephrine in suppressing peristalsis. ConclusionsThis 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.

Perioperative myocardial cell injury: The relationship between troponin t and cortisol

STUDY OBJECTIVE To investigate whether there is an association between Troponin T (TnT), reflecting myocardial cell injury, and cortisol, reflecting the degree of surgical trauma and associated stress, in light of our recent evaluation of TnT as a marker of perioperative myocardial cell injury. DESIGN Prospective, cohort study. PATIENTS 70 patients (67.4 +/- 8.7 yrs) with definite or at-risk coronary artery disease (CAD) undergoing elective noncardiac surgery (vascular n = 38, abdominal n = 21, orthopedic n = 8) with general (n = 63) or regional (n = 4) anesthesia with postoperative on-demand analgesia. MEASUREMENTS AND MAIN RESULTS Morning blood samples for TnT (upper limit of normal: <0.2 ng/mL), CK-MB (reference range </=12 U/L), and cortisol (normal morning range 7-25 mcg/dL) were taken on the day before surgery, on the morning of surgery before induction of anesthesia, and on the first 5 postoperative days. Data were compared by analysis of variance. Three patients were excluded from the study because of incomplete blood samples of TnT or cortisol. Preoperative mean cortisol levels (mcg/dL +/- SD) were within the normal range and equal in TnT positive (n = 13) and negative (n = 54) patients (16.1 +/- 4.5 vs. 15.6 +/- 5.8). On the 1st postoperative day, there was a substantial increase of cortisol in the TnT positive group (35.7 +/- 26.9). Cortisol remained high until the 5th postoperative day (24.7 +/- 9. 4). There was a significant difference in the cortisol concentration in TnT-positive compared to TnT-negative patients (p < 0.001), a significant difference in the perioperative cortisol concentration over time (p < 0.05), and a significant interaction (p < 0.001). But there was no consistent temporal relationship between the increase of TnT and the increase of cortisol. CONCLUSIONS The significant relationship between a highly sensitive and specific marker of myocardial cell injury and a marker of stress suggests that cardiac-risk patients undergoing stressful surgical procedures might benefit from close perioperative TnT monitoring with early recognition of myocardial cell injury.

Serum 1,3-beta-d-glucan for antifungal treatment stratification at the intensive care unit and the influence of surgery

The purpose of this study was to evaluate a preemptive approach with serum 1,3‐beta‐d‐glucan (BDG) as a marker for treatment stratification of systemic antifungal (AF) therapy in patients with clinical suspected invasive fungal infections (IFI) at intensive care units (ICU), and the impact of surgical procedures. A total of 66 ICU patients with clinical suspected IFI were included in this retrospective analysis. Serum BDG testing was performed prior to initiation of AF treatment and in addition to routine diagnostic measures. Based on the BDG results the initial clinical decision whether or not to start systemic AF therapy was re‐evaluated. Impact of surgical procedures on clinical utility of serum BDG was evaluated in a sub‐group of 25 patients who had undergone surgical procedures prior to BDG evaluation. BDG test results led to discontinuation of AF therapy in 13 patients, and initiation of AF therapy in seven patients. In 46 patients the clinical decision was confirmed by BDG. The majority of suspected, probable and proven IFI cases (10/13, 77%) was predicted by the test. BDG testing turned out positive in 9/25 (36%) of patients that had undergone recent surgery and levels correlated with clinical findings. Serum BDG evaluation seems to be a promising tool to guide AF therapy in ICU patients even after recent surgical procedures.

Effect of ICU interventions on gastrointestinal motility

Purpose of reviewEarly detection of gastrointestinal motility disturbances is a major goal to reduce the incidence of this potentially disastrous event by prophylactic managements and early goal-directed therapy in patients at risk. Recent findingsGastroparesis frequently results in the inability to feed critically ill patients, aggravating problems such as bacterial translocation and stress-induced intestinal damage. Recently published data have advanced our understanding of the pathophysiologic background of gastroparesis, intestinal stress damage and the effect of early enteral nutrition on gastrointestinal function. New techniques, such as ultrasound and the capsule techniques, might help to assess intestinal function beyond the aspiration of gastric residual volumes and the passage of stool. Therapeutic options such as opioid antagonists and the 5-hydroxytryptamine receptor 4 agonist prucalopride might help to restore intestinal function. SummaryGastrointestinal motility disturbances are caused by a myriad of pathological processes. Moreover, bowel integrity is governed by comorbidity, impaired metabolic function and pharmacological interventions in critically ill patients. Restoring gastrointestinal function, therefore, requires a multimodal approach including prophylactic management strategies and the sensible use of substances with inhibitory effects on intestinal motility.

Long-term outcome and prognostic factors in dilated cardiomyopathy : preliminary results

To investigate long-term follow-up and identify prognostic factors in patients with dilated cardiomyopathy (DCM) the authors investigated 167 consecutive patients on an outpatient basis. All patients underwent left- and right-heart catheterization; follow-up comprised clinical and echocardiographic investigations. Results: After a mean follow-up period of ninety-three ± thirty-six months 82 patients (49%; 71 men, 11 women, mean age fifty-five ± eleven years) were alive. 29 of them (27 men, 2 women, mean age fifty-two ± nine) showed normal left ventricular ejection fraction (LVEF) after a mean follow-up period of one hundred four ± forty months. The remaining 53 patients (44 men, 9 women, mean age fifty-six ± eleven) revealed LVEF similar to that of the first examination. Eighty-five patients died (51%; 73 men, 12 women). Causes of death were the following: progressive heart failure, 24; sudden death, 23; stroke, 3; pulmonary embolism, 2; noncardiac death, 4; unknown causes, 29. The median period from the onset of first symptoms until definite diagnosis was two months in patients with stable conditions, three months in those with normalization of LVEF and twenty-four months in those who died, respectively (P < 0.01). At the time of diagnosis, patients with stable outcome had a mean LVEF (LVEF 1) of 37%, those who returned to normal had 40% (ns). Patients who died had a mean LVEF 1 of 32% and therefore differed significantly from both groups of survivors (P < 0.001). Left ventricular enddiastolic pressure (LVEDP) at the time of diagnosis was highest in patients who died (22 mmHg) and therefore differed significantly from both groups of survivors (normalization: 16 mmHg, stable patients: 18 mmHg, P < 0.001). Conclusions: According to their results, time until diagnosis, LVEF, and LVEDP are prognostic indicators. No difference was noted between the groups concerning etiology, medical treatment, or functional classification according to the New York Heart Association.

Endotoxin pretreatment modifies peristalsis and attenuates the antipropulsive action of adrenoceptor agonists in the guinea-pig small intestine

Abstract  The action of endotoxin to alter gastrointestinal motility in vivo may reflect a direct effect on the gut or result from vascular and other systemic manifestations of this sepsis model. Here we examined whether in vivo pretreatment of guinea‐pigs with endotoxin modifies peristalsis in the isolated gut and influences the antipropulsive action of adrenoceptor agonists. Distension‐induced peristalsis was recorded in fluid‐perfused segments of the small intestine taken from animals pretreated intraperitoneally with endotoxin (1 mg kg−1Escherichia coli lipopolysaccharide) or vehicle 4 or 20 h before. Clonidine, adrenaline, noradrenaline, dopamine and dobutamine inhibited peristalsis with differential potency. Endotoxin pretreatment lowered the peristaltic pressure threshold and altered other parameters of baseline peristalsis in a time‐related manner. The potency and efficacy of clonidine to inhibit peristalsis were markedly decreased after endotoxin administration, while the potency of the other test drugs was less attenuated. The antipropulsive action of clonidine in control segments was reduced by yohimbine and prazosin, whereas in segments from endotoxin‐pretreated animals it was antagonized by yohimbine but not prazosin. We conclude that systemic endotoxin pretreatment of guinea‐pigs modifies baseline peristalsis by an action on the gut and inhibits the antipropulsive action of adrenoceptor agonists through changes in adrenoceptor activity.