Thomas Scheeren

Plasma nitrite reflects constitutive nitric oxide synthase activity in mammals

Changes in plasma nitrite concentration in the human forearm circulation have recently been shown to reflect acute changes in endothelial nitric oxide synthase (eNOS)-activity. Whether basal plasma nitrite is a general marker of constitutive NOS-activity in vivo is yet unclear. Due to the rapid metabolism of nitrite in blood and the difficulties in its analytical determination literature data on levels of nitrite in mammals are largely inconsistent. We hypothesized that constitutive NOS-activity in the circulatory system is relatively uniform throughout the mammalian kingdom. If true, this should result in comparable systemic plasma nitrite levels in different species. Using three different analytical approaches we determined plasma nitrite concentration to be in a nanomolar range in a variety of species: humans (305 +/- 23 nmol/l), monkeys (367 +/- 62 nmol/l), minipigs (319 +/- 24 nmol/l), dogs (305 +/- 50 nmol/l), rabbits (502 +/- 21 nmol/l), guinea pigs (412 +/- 44 nmol/l), rats (191 +/- 43 nmol/l), and mice (457 +/- 51 nmol/l). Application of different NOS-inhibitors in humans, minipigs, and dogs decreased NOS-activity and thereby increased vascular resistance. This was accompanied by a significant, up to 80%, decrease in plasma nitrite concentration. A comparison of plasma nitrite concentrations between eNOS(-/-) and NOS-inhibited wild-type mice revealed that 70 +/- 5% of plasma nitrite is derived from eNOS. These results provide evidence for a uniform constitutive vascular NOS-activity across mammalian species.

Monitoring tissue oxygenation by near infrared spectroscopy (NIRS): background and current applications.

Conventional cardiovascular monitoring may not detect tissue hypoxia, and conventional cardiovascular support aiming at global hemodynamics may not restore tissue oxygenation. NIRS offers non-invasive online monitoring of tissue oxygenation in a wide range of clinical scenarios. NIRS monitoring is commonly used to measure cerebral oxygenation (rSO2), e.g. during cardiac surgery. In this review, we will show that tissue hypoxia occurs frequently in the perioperative setting, particularly in cardiac surgery. Therefore, measuring and obtaining adequate tissue oxygenation may prevent (postoperative) complications and may thus be cost-effective. NIRS monitoring may also be used to detect tissue hypoxia in (prehospital) emergency settings, where it has prognostic significance and enables monitoring of therapeutic interventions, particularly in patients with trauma. However, optimal therapeutic agents and strategies for augmenting tissue oxygenation have yet to be determined.

A review of postoperative cognitive dysfunction and neuroinflammation associated with cardiac surgery and anaesthesia

Postoperative cognitive dysfunction is receiving increasing attention, particularly as it mainly affects the (growing) elderly population. Until recently, cognitive deficits after cardiac surgery were thought to be caused by physiological disturbances associated with the cardiopulmonary bypass technique. Although the technique of ‘off‐pump’ coronary revascularisation may potentially be associated with improved outcome, long‐term follow‐up studies have failed to demonstrate a significant reduction in the incidence of postoperative cognitive dysfunction. The focus of research is thus shifting from cardiopulmonary bypass to other factors common to both techniques, such as surgery, anaesthesia and patient‐related predisposing factors. Priming of the immune system by ageing and atherosclerosis may result in an exaggerated systemic and cerebral inflammatory response to cardiac surgery and anaesthesia, causing neuronal loss or dysfunction resulting in cognitive dysfunction. We briefly discuss the evidence for cardiopulmonary bypass‐related neuronal injuries in adult cardiac surgery patients, and review the evidence that immune priming is a key factor in the pathogenesis of cognitive dysfunction after cardiac surgery.

Prostacyclin (PGI2): new aspects of an old substance in the treatment of critically ill patients

It is now 20 years since Moncada and Vane discovered prostaglandin I2 (PGI2) [1] and named it “prostacyclin”. Since then, interest in the theoretical background and clinical application of this natural agent has increased continuously. This review summarizes the pharmacological properties and endogenous role of PGI2. Furthermore, clinical applications (in particular of its analogue epoprostenol) are discussed, with special emphasis on the treatment of critically ill patients suffering from sepsis and/or pulmonary hypertension, either associated with the acute respiratory distress syndrome (ARDS) or of other origin (e. g., after cardiac surgery). In this context we also point out recent advances concerning the transbronchial delivery route as opposed to intravenous infusion and compare its effects to that of nitric oxide (NO) inhalation.

A Phase 3 Randomized Double-Blind Comparison of Ceftobiprole Medocaril Versus Ceftazidime Plus Linezolid for the Treatment of Hospital-Acquired Pneumonia

BACKGROUND Ceftobiprole, the active moiety of ceftobiprole medocaril, is a novel broad-spectrum cephalosporin, with bactericidal activity against a wide range of gram-positive bacteria, including Staphylococcus aureus (including methicillin-resistant strains) and penicillin- and ceftriaxone-resistant pneumococci, and gram-negative bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa. METHODS This was a double-blind, randomized, multicenter study of 781 patients with hospital-acquired pneumonia (HAP), including 210 with ventilator-associated pneumonia (VAP). Treatment was intravenous ceftobiprole 500 mg every 8 hours, or ceftazidime 2 g every 8 hours plus linezolid 600 mg every 12 hours; primary outcome was clinical cure at the test-of-cure visit. RESULTS Overall cure rates for ceftobiprole vs ceftazidime/linezolid were 49.9% vs 52.8% (intent-to-treat [ITT], 95% confidence interval [CI] for the difference, -10.0 to 4.1) and 69.3% vs 71.3% (clinically evaluable [CE], 95% CI, -10.0 to 6.1). Cure rates in HAP (excluding VAP) patients were 59.6% vs 58.8% (ITT, 95% CI, -7.3 to 8.8), and 77.8% vs 76.2% (CE, 95% CI, -6.9 to 10.0). Cure rates in VAP patients were 23.1% vs 36.8% (ITT, 95% CI, -26.0 to -1.5) and 37.7% vs 55.9% (CE, 95% CI, -36.4 to 0). Microbiological eradication rates in HAP (excluding VAP) patients were, respectively, 62.9% vs 67.5% (microbiologically evaluable [ME], 95% CI, -16.7 to 7.6), and in VAP patients 30.4% vs 50.0% (ME, 95% CI, -38.8 to -0.4). Treatment-related adverse events were comparable for ceftobiprole (24.9%) and ceftazidime/linezolid (25.4%). CONCLUSIONS Ceftobiprole is a safe and effective bactericidal antibiotic for the empiric treatment of HAP (excluding VAP). Further investigations are needed before recommending the use of ceftobiprole in VAP patients. Clinical Trials Registration. NCT00210964, NCT00229008.

Levosimendan is superior to milrinone and dobutamine in selectively increasing microvascular gastric mucosal oxygenation in dogs.

Objective:The effect of levosimendan, a novel inotropic vasodilator (inodilator), on the microvascular gastric mucosal hemoglobin oxygenation (&mgr;Hbo2) is unknown. A possible effect could thereby be selective for the splanchnic region or could primarily reflect changes in systemic oxygen transport (&U1E0A;o2) and/or oxygen consumption (&OV0312;o2). We compared systemic and regional effects of levosimendan with those of established inotropes, milrinone and dobutamine. Design:Laboratory experiment. Setting:University animal research laboratory of experimental anesthesiology. Subjects:Chronically instrumented dogs with flow probes for cardiac output measurement. Interventions:Anesthetized, mechanically ventilated dogs (each group n = 6) on different days randomly received levosimendan (10 &mgr;g·kg−1, followed by four infusion steps: 0.125–1.0 &mgr;g·kg−1·min−1), milrinone (5.0 &mgr;g·kg−1, followed by 1.25–10 &mgr;g·kg−1·min−1), or dobutamine (2.5–10.0 &mgr;g·kg−1·min−1). Since these drugs may modify regional or systemic responses to fluid load, an additional predefined volume challenge was subsequently performed with hydroxyethyl starch 6% (10 mL·kg−1). Measurements and Main Results:We measured &mgr;Hbo2 (reflectance spectrophotometry), &U1E0A;o2, &OV0312;o2, and systemic hemodynamics. Levosimendan significantly increased &mgr;Hbo2 from baseline (∼55% for all groups) to 64 ± 4% and further to 69 ± 2% with volume challenge (mean ± sem). At the systemic level, levosimendan alone only slightly increased &U1E0A;o2 at a stable &OV0312;o2. Milrinone elicited similar systemic effects (&U1E0A;o2, &OV0312;o2, hemodynamics) but failed to increase &mgr;Hbo2. Dobutamine, conversely, increased &mgr;Hbo2 to a similar extent as levosimendan; however, this was accompanied by marked increases in &U1E0A;o2 and &OV0312;o2. The gastric mucosa selectivity of these interventions, expressed as slope of the &mgr;Hbo2/&U1E0A;o2 relation, was highest for levosimendan (+1.89 and +1.14, without and with volume challenge), compared with milrinone (+0.45 and + 0.47) and dobutamine (+0.48 and + 0.33). Conclusions:Levosimendan is superior to milrinone (no significant regional effects) and dobutamine (marked systemic effects) in increasing gastric mucosal oxygenation selectively (i.e., at only moderately increased &U1E0A;o2 and stable &OV0312;o2). If our experimental data apply to the clinical setting, levosimendan may serve as an option to selectively increase gastrointestinal mucosa oxygenation in patients at risk to develop splanchnic ischemia.

Less invasive hemodynamic monitoring in critically ill patients

Over the last decade, the way to monitor hemodynamics at the bedside has evolved considerably in the intensive care unit as well as in the operating room. The most important evolution has been the declining use of the pulmonary artery catheter along with the growing use of echocardiography and of continuous, real-time, minimally or totally non-invasive hemodynamic monitoring techniques. This article, which is the result of an agreement between authors belonging to the Cardiovascular Dynamics Section of the European Society of Intensive Care Medicine, discusses the advantages and limits of using such techniques with an emphasis on their respective place in the hemodynamic management of critically ill patients with hemodynamic instability.

Clinical review : use of venous oxygen saturations as a goal - a yet unfinished puzzle

Shock is defined as global tissue hypoxia secondary to an imbalance between systemic oxygen delivery and oxygen demand. Venous oxygen saturations represent this relationship between oxygen delivery and oxygen demand and can therefore be used as an additional parameter to detect an impaired cardiorespiratory reserve. Before appropriate use of venous oxygen saturations, however, one should be aware of the physiology. Although venous oxygen saturation has been the subject of research for many years, increasing interest arose especially in the past decade for its use as a therapeutic goal in critically ill patients and during the perioperative period. Also, there has been debate on differnces between mixed and central venous oxygen saturation and their interchangeability. Both mixed and central venous oxygen saturation are clinically useful but both variables should be used with insightful knowledge and caution. In general, low values warn the clinician about cardiocirculatory or metabolic impairment and should urge further diagnostics and appropriate action, whereas normal or high values do not rule out persistent tissue hypoxia. The use of venous oxygen saturations seems especially useful in the early phase of disease or injury. Whether venous oxygen saturations should be measured continuously remains unclear. Especially, continuous measurement of central venous oxygen saturation as part of the treatment protocol has been shown a valuable strategy in the emergency department and in cardiac surgery. In clinical practice, venous oxygen saturations should always be used in combination with vital signs and other relevant endpoints.

Peep Decreases Oxygenation of the Intestinal Mucosa Despite Normalization of Cardiac Output

OBJECTIVE To evaluate if normalization of cardiac output reverses the attenuation of local intracapillary hemoglobin saturation (HbO2) of gastric mucosa by PEEP (positive end-expiratory pressure) during IPPV (intermittent positive pressure ventilation). MATERIALS AND METHODS Four healthy, chronically instrumented, anesthetized dogs were repeatedly studied (n = 7). Local HbO2 of gastric mucosa was measured continuously by tissue lightguide spectrophotometry and cardiac output (CO) was recorded continuously by means of a precalibrated ultrasonic transit time flowmeter chronically implanted around the pulmonary artery. After obtaining baseline values during IPPV and ZEEP (zero end-expiratory pressure) 15 cmH2O PEEP was added. To compensate the reduction of CO during PEEP ventilation, HES (hydroxyethyl starch 6%) was infused until CO reached baseline values during ZEEP. RESULTS Despite of unimpaired systemic oxygen saturation, PEEP reduced HbO2 of gastric mucosa from 55.1 +/- 4.2% to 42.1 +/- 4.7% (mean +/- SEM) and CO dropped from 67.7 +/- 4.9 ml.kg-1.min-1 to 33.9 +/- 4.6 ml.kg-1.min-1. Whereas infusion of HES during PEEP ventilation normalized CO to 65.1 +/- 6.2 ml.kg-1.min-1, HbO2 reached only 48.1 +/- 3.3%, a statistically significant improvement compared to HbO2 during PEEP ventilation before HES infusion (p < 0.03, Wilcoxon signed rank test), but still below baseline values (p < 0.04). CONCLUSIONS Our findings demonstrate that the side effects of PEEP ventilation on cardiac output can be compensated by restoring preload, but normalizing CO did not completely normalize HbO2 of the gastric mucosa. This further emphasizes that global measurements of variables of systemic circulation and oxygenation do not necessarily reflect regional abnormalities of tissue oxygenation. Therefore, in view of the importance of tissue hypoxia especially in the splanchnic region in the pathogenesis of multiple organ failure, monitoring of HbO2 of the intestinal mucosa during PEEP ventilation may be particularly useful in the care of the critically ill patient.

Desflurane inhibits hypoxic pulmonary vasoconstriction in isolated rabbit lungs.

Background Inhalational anesthetics inhibit hypoxic pulmonary vasoconstriction (HPV) in vivo and in vitro with a half-maximum inhibiting effect (ED50) within concentrations applied for general anesthesia. Because it is unknown whether desflurane acts likewise, we studied its effect on HPV in isolated blood-perfused rabbit lungs and compared its ED sub 50 with that of halothane.