Structured information during the ICU stay to reduce anxiety: study protocol of a multicenter randomized controlled trial.

BACKGROUND: ICU stay is often associated with negative experiences for the individual patient. Many patients are disabled and their communication is restricted during the ICU stay. Specific information on procedures, sensations and coping behavior are thought to reduce anxiety on the ICU. Until now information programs to reduce anxiety were mainly delivered preoperatively, completely neglecting informational needs of non-elective ICU patients. METHODS: The trial is designed as a prospective multicenter randomized controlled trial in the cities of Marburg, Halle and Stuttgart. Elective and non-elective ICU patients will be included. The trial includes an intervention and a control group on the ICU. The control group receives a trivial conversation without any ICU-specific information. The intervention group receives an information program with specific procedural, sensory and coping information about their ICU stay. Both conversations take place in the ICU and are planned to take about 10 minutes. DISCUSSION: In contrast to former trials on information programs on the ICU-stay our intervention will take place in the ICU itself. This approach will ensure to compensate for memory effects due to anesthesia or preoperative stress. Further the results will be applicable to non-elective ICU-patients. TRIAL REGISTRATION: ClinicalTrials NCT00764933.

Development and validation of an efficient HPLC method for quantification of voriconazole in plasma and microdialysate reflecting an important target site.

Voriconazole is a very potent antifungal agent used to treat serious fungal infections (candidiasis); it is also the therapy of choice for aspergillosis. After standard dosing, several factors affect exposure of voriconazole, resulting in large variability and demanding further elucidation of drug distribution. For measurements at the site of action, microdialysis is considered to be an outstanding minimally invasive method. For determination of voriconazole in microdialysate and human plasma a new, efficient, reliable, and robust HPLC assay using UV detection at 254 nm has been developed and validated. After simple sample preparation using acetonitrile for plasma and for microdialysate, 20 microL were injected and separated on an RP-18 column. The chromatographic run time was less than 4 min. Overall, the assay showed high precision (CV 93.9 to 99.5%) and accuracy (RE -96.7 to +107%) for both matrices. Of the 36 drug products typically co-administered with voriconazole, none except ambroxol interfered with its peak signal, and this interference was successfully managed. In summary, the method is highly suitable for application in (pre)clinical microdialysis studies, e.g., of critically ill patients with invasive mycoses.

Selenium in Intensive Care (SIC): results of a prospective randomized, placebo-controlled, multiple-center study in patients with severe systemic inflammatory response syndrome, sepsis, and septic shock.

OBJECTIVE: Sepsis is associated with an increase in reactive oxygen species and low endogenous antioxidative capacity. We postulated that high-dose supplementation of sodium-selenite would improve the outcome of patients with severe sepsis and septic shock. DESIGN: Prospective randomized, placebo-controlled, multiple-center trial. SETTING: Eleven intensive care units in Germany. PATIENTS: Patients were 249 patients with severe systemic inflammatory response syndrome, sepsis, and septic shock and an Acute Physiology and Chronic Health Evaluation (APACHE) III score >70. INTERVENTIONS: Patients received 1000 microg of sodium-selenite as a 30-min bolus injection, followed by 14 daily continuous infusions of 1000 microg intravenously, or placebo. MEASUREMENTS AND MAIN RESULTS: The primary end point was 28-day mortality; secondary end points were survival time and clinical course of APACHE III and logistic organ dysfunction system scores. In addition, selenium levels in serum, whole blood, and urine as well as serum glutathione-peroxidase-3 activity were measured. From 249 patients included, 11 patients had to be excluded. The intention-to-treat analysis of the remaining 238 patients revealed a mortality rate of 50.0% in the placebo group and 39.7% in the selenium-treated group (p = .109; odds ratio, 0.66; confidence interval, 0.39-1.1). A further 49 patients had to be excluded before the final analysis because of severe violations of the study protocol. In the remaining 92 patients of the study group, the 28-day mortality rate was significantly reduced to 42.4% compared with 56.7% in 97 patients of the placebo group (p = .049, odds ratio, 0.56; confidence interval, 0.32-1.00). In predefined subgroup analyses, the mortality rate was significantly reduced in patients with septic shock with disseminated intravascular coagulation (n = 82, p = .018) as well as in the most critically ill patients with an APACHE III score > or =102 (>75% quartile, n = 54, p = .040) or in patients with more than three organ dysfunctions (n = 83, p = .039). Whole blood selenium concentrations and glutathione peroxidase-3 activity were within the upper normal range during selenium treatment, whereas they remained significantly low in the placebo group. There were no side effects observed due to high-dose sodium-selenite treatment. CONCLUSIONS: The adjuvant treatment of patients with high-dose sodium-selenite reduces mortality rate in patients with severe sepsis or septic shock.

Skin function parameters in intensive-care patients.

BACKGROUND/PURPOSE: The study was performed to investigate the transepidermal water loss (TEWL) and pH-value in patients in intensive care. METHODS: Forty intensive-care patients (22 men, 18 women) were included in the study. TEWL and pH-values were measured at admission, and after 24, 96 and 168 h. The areas of measurement were the forehead, the volar forearm, paraumbilical and the ventral thigh. The measurements were made under standardized environmental conditions according to the recommendations of the EMCO Group. RESULTS: Elevated values were found on the forehead compared with the other skin areas examined. There was no significant change in mean TEWL-values in any patient in the course of the study. There was also no significant influence of TEWL at the time of admission on the prognosis. The course analysis of the mean pH-values, however, showed that patients who developed a systemic inflammatory response syndrome (SIRS) or sepsis during the further course had a higher pH-value over the entire study period. CONCLUSION: TEWL and the pH of the skin surface could be measured at bedside in the intensive-care unit and delivered reproducible results. These parameters appear, however, to be relevant only for subgroups of patients under intensive care.

Surgical trauma affects the proinflammatory status after cardiac surgery to a higher degree than cardiopulmonary bypass.

OBJECTIVES: Cytokines contribute to the development of the systemic inflammatory response syndrome or multiple-organ failure frequently observed after cardiopulmonary bypass-supported cardiac surgery. To quantify the contribution of bypass-induced versus trauma-induced inflammatory response after coronary artery bypass grafting, we examined plasma cytokine levels in 120 patients with coronary artery disease who were treated with or without cardiopulmonary bypass-assisted procedures. METHODS: Patients were treated in accordance with one of the following protocols: (1) elective percutaneous coronary intervention without cardiopulmonary bypass (n = 69), (2) cardiopulmonary bypass-supported percutaneous coronary intervention (cardiopulmonary bypass-percutaneous coronary intervention; n = 10), and (3) cardiopulmonary bypass-supported coronary artery bypass grafting (cardiopulmonary bypass-coronary artery bypass grafting; n = 41). Cytokine levels (picograms/milliliter) were measured by enzyme-linked immunosorbent assay from plasma samples obtained at various time points. RESULTS: Interleukin-6 was measured in blood samples from all 3 patient populations. The maximum interleukin-6 level was 13.6 +/- 22.3 pg/mL in the percutaneous coronary intervention group, 170.4 +/- 165.4 pg/mL in the cardiopulmonary bypass-percutaneous coronary intervention group, and 640.3 +/- 285.7 pg/mL in the cardiopulmonary bypass-coronary artery bypass grafting group. Interleukin-6 levels were significantly different, and the 95% confidence intervals did not overlap. In the cardiopulmonary bypass-percutaneous coronary intervention group, bypass duration correlated well with interleukin-6 production ( r = 0.915; P < .001), whereas these parameters did not correlate in patients who underwent cardiopulmonary bypass-coronary artery bypass grafting ( r = 0.307; P = .054). CONCLUSIONS: These findings support the suggestion that surgical trauma and cardiopulmonary bypass contribute to the inflammatory response after cardiac surgery, although trauma may contribute to a higher degree.

Influence of moderate and profound hyperventilation on cerebral blood flow, oxygenation and metabolism.

OBJECTIVE: The aim of the present study was to examine the impact of moderate and profound hyperventilation on regional cerebral blood flow (rCBF), oxygenation and metabolism. MATERIALS AND METHODS: Twelve anesthetized pigs were subjected to moderate (mHV) and profound (pHV) hyperventilation (target arterial pO(2): 30 and 20 mmHg, respectively) for 30 min each, after baseline normoventilation (BL) for 1 h. Local cerebral extracellular fluid (ECF) concentrations of glucose, lactate, pyruvate and glutamate as well as brain tissue oxygenation (p(ti)O(2)) were monitored using microdialysis and a Licox oxygen sensor, respectively. In nine pigs, regional cerebral blood flow (rCBF) was also continuously measured via a thermal diffusion system. RESULTS: Both moderate and profound hyperventilation resulted in a significant decrease in rCBF (BL: 37.9+/-4.3 ml/100 g/min; mHV: 29.4+/-3.6 ml/100 g/min; pHV: 23.6+/-4.7 ml/100 g/min; p<0.05) and p(ti)O(2) (BL: 22.7+/-4.1 mmHg; mHV: 18.9+/-4.9 mmHg; pHV: 13.0+/-2.2 mmHg; p<0.05). A p(ti)O(2) decrease below the critical threshold of 10 mmHg was induced in three animals by moderate hyperventilation and in five animals by profound hyperventilation. Furthermore, significant increases in lactate (BL: 1.06+/-0.18 mmol/l; mHV: 1.36+/-0.20 mmol/l; pHV: 1.67+/-0.17 mmol/l; p<0.005), pyruvate (BL: 46.4+/-7.8 micromol/l; mHV: 58.0+/-10.3 micromol/l; pHV: 66.1+/-12.7 micromol/l; p<0.05), and lactate/glucose ratio were observed during hyperventilation. (Data are presented as mean+/-S.E.M.) CONCLUSIONS: Both moderate and profound hyperventilation may result in insufficient regional oxygen supply and anaerobic metabolism, even in the uninjured brain. Therefore, the use of hyperventilation cannot be considered as a safe procedure and should either be avoided or used with extreme caution.

Reliability of the NeuroTrend sensor system under hyperbaric conditions.

OBJECTIVE: The goal of this study was to investigate the reliability of the multi-parameter sensor NeuroTrend in a hyperbaric environment for up to 3bar absolute pressure. Measurement of brain tissue oxygenation (ptiO2) under hyperbaric conditions is supposed to elucidate whether hyperbaric oxygenation therapy has the potential to improve ptiO2 to a clinically significant degree in pathological altered brain tissue after traumatic brain injury. METHODS: The NeuroTrend sensor hose, filled with equilibrated plasma samples, was stored in a decompression chamber. The plasma samples were equilibrated with three different gas mixtures. After determination of the initial values for temperature, oxygen partial pressure (pO2), carbon dioxide partial pressure (pCO2) and hydrogen ion concentration (pH) in the plasma, the ambient pressure was stepwise increased from 0.1 to 3 bar. The same set-up was performed without increasing the ambient pressure. RESULTS: No significant difference in the mean values for all 23 measurement points and for all parameters (pO2, pCO2, pH) of all 10 NeuroTrend sensors was found, under both normobaric and hyperbaric conditions. CONCLUSION: The study demonstrated that an absolute ambient pressure up to 3 bar did not influence the measuring properties and the reliability of the NeuroTrend sensor.

Thr164Ile polymorphism of the human beta2-adrenoceptor exhibits blunted desensitization of cardiac functional responses in vivo.

In subjects heterozygous for Thr164Ile beta2-adrenoceptor (beta2AR) polymorphism, cardiac responses to beta2AR agonist stimulation are blunted. In this study, we investigated agonist-induced desensitization of Thr164Ile beta2ARs. For this purpose, we assessed in six subjects with heterozygous Thr164Ile beta2ARs and in 10 subjects with homozygous wild-type (WT) beta2ARs the effects of 2-wk oral treatment with 3 x 5 mg/day terbutaline on terbutaline infusion-induced increases in heart rate (HR) and contractility [measured as shortening of HR-corrected duration of electromechanical systole (QS2c)]. Compared with WT beta2AR subjects, Thr164Ile subjects exhibited a blunted terbutaline-induced maximum increase in HR (WT 32 +/- 4 beats/min, Thr164Ile 19 +/- 3 beats/min, P < 0.05) and contractility (WT -54 +/- 2 ms, Thr164Ile -37 +/- 6 ms, P < 0.05). Two-week oral terbutaline treatment desensitized cardiac beta2AR responses to terbutaline infusion (increase in HR: WT 10 +/- 2 beats/min, Thr164Ile 8 +/- 4 beats/min; increase in contractility: WT -22 +/- 5 ms Thr164Ile: -17 +/- 6 ms); however, the extent of desensitization was larger in WT than Thr164Ile beta2AR subjects. Thus, after 2-wk oral terbutaline treatment cardiac, beta2AR responses did not differ anymore between WT and Thr164Ile beta2AR subjects. We conclude that agonist-induced desensitization of cardiac beta2ARs is more pronounced in WT than Thr164Ile subjects. Thus cardiac Thr164Ile subjects appear to be somewhat protected against agonist-induced desensitization.

Effects of atropine on human cardiac beta 1- and/or beta 2-adrenoceptor stimulation.

The aim of this study was to find out whether, in humans, the increase in vagal tone accompanying cardiac beta-adrenoceptor (beta-AR) stimulation might be different dependent on beta1- or beta2-AR stimulation. For this purpose we studied, in six male healthy volunteers (aged 28+/-1 years), the effects of atropine infusion (0.15 microg/kg/min continuously) on increase in heart rate (HR) and contractility (determined as shortening of HR-corrected duration of electromechanical systole-QS2c) evoked by infusion of isoprenaline (3.5-35 ng/kg/min, increasing HR and QS2c via beta1-and beta2-AR), terbutaline (25-150 ng/kg/min, increasing HR and QS2c via beta2-AR), adrenaline (20-160 ng/kg/min, increasing HR via beta2-and QS2c via beta1-AR) and bicycle exercise in supine position (increasing HR and QS2c via beta1-AR). The three beta-AR agonists and exercise increased HR and shortened QS2c in a dose- or work-load-dependent manner, respectively. Atropine enhanced HR-increasing effects of all three beta-AR agonists and exercise; increases were larger for beta2-AR (terbutaline, adrenaline) mediated effects than for beta1-AR (exercise) mediated effects. Moreover, atropine enhanced beta-AR agonists-induced QS2c shortening; however, atropine effects on QS2c were markedly less pronounced than on HR. From the results we conclude that, in humans, beta1-and beta2-AR mediated stimulation evoked HR-increases are composed of two components: increases via direct beta-AR stimulation and simultaneously decreases via increase in vagal tone. In addition, beta-AR mediated increases in contractility are also dampened by simultaneous activation of vagal tone but to a lesser extent possibly because human ventricular myocardium is only sparsely parasympathetically innervated.

The Gln27Glu beta2-adrenoceptor polymorphism slows the onset of desensitization of cardiac functional responses in vivo.

Studies performed have shown that the Arg16Gly allele in beta-adrenoceptors (beta2AR) enhances susceptibility to agonist-induced down-regulation, while the Gln27Glu polymorphism diminishes it. In this study, we tested whether similar phenotypes occur in vivo. We assessed 32 volunteers (mean age 25 +/- 2 years) with different genotypes (group A: wild-type beta2AR, n = 16; group B: homozygous Glu27, n = 10; group C: homozygous Gly16, n = 6) for the effect of 2 weeks treatment with 3 x 5 mg/day oral terbutaline on terbutaline infusion-induced increases in heart rate and contractility (i.e. shortening of heart rate-corrected duration of electromechanical systole, QS2c). At baseline, terbutaline infusion increased heart rate and contractility similarly among subjects in the three groups. Treatment with oral terbutaline for 14 days reduced the ability of intravenous (i.v.) terbutaline to increase heart rate and contractility. The extent of this reduction was similar but the time course of desensitization differed among the three groups. While in groups A and C terbutaline infusion-induced increases in heart rate and contractility were reduced within 24 h after oral ingestion of terbutaline, a significant effect on response to terbutaline infusion was not evident for the first 3 days of terbutaline treatment in group B. The Arg16Gly and the Gln27Glu variants of the beta2AR do not alter the extent of agonist-induced beta2AR desensitization in vivo but Glu27 homozygotes develop desensitization more slowly. This result may have implications for cardiac side-effects in patients who are Glu27 homozygotes and who receive beta2AR agonist therapy.