ß-(1→3)-D-glucan- and mannan-guided early termination of antifungal therapy in ICU patients: a randomized controlled study.

Candida spp. are frequently encountered in specimens from ICUs. However, most of these detections represent colonization. Nevertheless, clinical practice shows that a considerable proportion of these patients will receive antifungal therapy (AT). ß-(1→3)-D-glucan (BDG) and mannan are fungal biomarkers with high negative predictive values. We aimed to examine whether biomarker-guided discontinuation of AT can reduce the antifungal consumption. Therefore, we conducted a prospective, randomized intervention study between 1 April 2019 and 31 March 2020. All adult ICU patients with a newly started systemic AT but without fungal infection were eligible for inclusion. Enrolled patients were randomized into an intervention and a control group. In both groups, serum BDG and mannan were determined on days 1 and 2 of AT. If all measurements were negative, AT was discontinued in the intervention group. The primary endpoint was antifungal use. The study was terminated after 12 months. Until this time-point, 41 patients had been included. In the intervention group (n = 19), AT was stopped in only two patients because all others showed either positive BDG and/or mannan levels. One of these two patients developed candidemia and AT had to be restarted. There was no significant difference in the primary and secondary endpoints. In summary, the strategy of using two negative BDG and mannan levels to stop AT failed to reduce antifungal consumption in our cohort. Indeed, there will inevitably be patients with invasive candidiasis in whom necessary AT is discontinued. The optimal patient population, biomarker set, and termination criteria are critical to the success of biomarker-based termination strategies.

Ethical conflicts associated with COVID-19 pandemic, triage and frailty-unexpected positive disease progression in a 90-year-old patient: A case report.

During the COVID 19 pandemic, advanced age, scoring systems, and a shortage of ICU beds were used as cut-offs for ICU admission. This case report describes the epicrisis of an elderly patient who was almost mistakenly not treated in an ICU.

Impact of the CYP3A5 genotype on midazolam pharmacokinetics and pharmacodynamics during intensive care sedation.

OBJECTIVE: Information is lacking on whether the CYP3A5 genotype affects the disposition and effects of midazolam during the long-term intensive care sedation of patients. This study was undertaken to estimate whether the CYP3A5 genotype can explain a relevant portion of pharmacokinetic interindividual variability. METHODS: We determined the CYP3A5 genotype in 71 Caucasian patients who underwent long-term sedation during intensive care treatment. We then assessed the relation between the genotype and both the plasma concentrations of midazolam and 1'-OH-midazolam in 645 plasma samples and the simultaneously estimated Ramsay sedation score, both of which were recorded during routine midazolam drug monitoring. RESULTS: Eight patients had the CYP3A5*1/*3 genotype and 63 patients the CYP3A5*3/*3 genotype. The concentration-dose ratio [C/D; plasma concentration of midazolam (ng/ml) divided by the rate of infusion (mg/h); expressed as the mean (95% confidence interval)] was 87.4 (70.8, 108.9) for the *3/*3 patients and 79.0 (48.9, 129.0) for *1/*3 patients. The corresponding data for infusion rate (IR; in mg/h), Ramsay score (RS) and the ratio 1'-OH-midazolam concentration/midazolam concentration (ROH) for *3/*3 and *1/*3 patients were IR 7.4 (6.2, 8.6) vs. 11.4 (4.9, 17.9), RS 5.4 (5.2, 5.6) vs. 5.3 (4.2, 6.0) and ROH 0.11 (0.09, 0.13) vs. 0.17 (0.11, 0.26), respectively. CONCLUSIONS: The CYP3A5*1/*3 genotype did not lead to an apparently lower midazolam concentration/dose ratio or Ramsay score values. As the present sedation procedure during intensive care therapy may be described as a physician closed-loop titration towards Ramsay scores of 4 +/- 1, our data do not indicate that prior determination of the genotype will result in better care or economic savings.

Midazolam therapeutic drug monitoring in intensive care sedation: a 5-year survey.

During a 5-year period, 1997 to 2002, therapeutic drug monitoring of midazolam plasma concentrations in combination with the level of sedation as assessed by the Ramsay sedation scale was performed in 648 critically ill patients requiring artificial ventilation. In a subgroup of 189 patients sepsis-related organ failure assessment procedure was additionally performed. A total number of 3354 samples were analyzed. Significantly reduced clearance of midazolam was observed within the first 4 days of midazolam treatment of critically ill patients. As a result, accumulation of midazolam and its metabolites occurred within the first week of treatment. In contrast, parameters such as serum bilirubin or creatinine, which are commonly used to adapt drug therapy to organ dysfunction, showed significant changes with a delay of more than 10 days as compared with the findings of midazolam monitoring. Midazolam plasma concentrations showed a good correlation with the sedative capacity of the drug (r2 = 0.906). However, a great variability of the drug effect between patients could be demonstrated, which, as a consequence, may complicate the development of dosing strategies based on midazolam plasma concentrations to better control sedation in critically ill patients. Furthermore, patient age seems to be an important factor for the considerable variability of the sedative effect of midazolam. To achieve a certain levels of sedation, significantly lower midazolam infusion rates as well as plasma concentrations were required as the patients age increased. No significant sex-related differences could be observed for any pharmacologic parameter obtained in this study. Our findings suggest that midazolam therapeutic drug monitoring might be a useful tool to individualize midazolam therapy, especially in critically ill patients developing organ dysfunction and requiring long-term sedation to minimize the risk of drug accumulation and excessive sedation.

Perioperative monitoring of circulating and central blood volume in cardiac surgery by pulse dye densitometry.

OBJECTIVE: To determine perioperative changes in circulating (BVI) and central blood volume (CBVI) by a new dye dilution technique using pulse dye densitometry. DESIGN AND SETTING: Prospective observational study in the cardiac anesthesia and intensive care unit of a university hospital. PATIENTS: Sixty-six patients undergoing coronary artery bypass surgery. MEASUREMENTS AND RESULTS: Hemodynamic measurements by the dye dilution method using pulse dye densitometry were performed prior to skin incision and 3.3+/-1.4 h and 17+/-2.7 h after surgery. Based on conventional monitoring the therapeutic goals of hemodynamic therapy were achieved in all of the patients of this study. Despite a marked positive fluid balance which developed during surgery mean BVI decreased significantly after surgery while CBVI remained unchanged. Postoperative BVI deficits vs. preoperative values were observed in 78% of patients; these BVI deficits were profound in 29% of the cases. In contrast, 65% of the individual patients showed no or only minor postoperative changes in CBVI vs. preoperative values. CONCLUSIONS: Changes in the intravascular volume compartments affected BVI to a greater extent than CBVI. Therefore measuring circulating in addition to central blood volume may be useful to ensure a normal circulating blood volume that can compensate for any change in the central vascular compartment.

Coincidence of pro- and anti-inflammatory responses in the early phase of severe sepsis: Longitudinal study of mononuclear histocompatibility leukocyte antigen-DR expression, procalcitonin, C-reactive protein, and changes in T-cell subsets in septic and postoperative patients.

OBJECTIVE: To determine the time course of histocompatibility leukocyte antigen (HLA)-DR expression in peripheral blood mononuclear cells and their relationship to markers of inflammation, organ function, and outcome during severe sepsis. DESIGN: Prospective, longitudinal study. SETTING: University hospital intensive care unit. PATIENTS: Twenty-three postoperative patients with severe sepsis and 26 patients with uneventful postoperative course as well as 24 healthy, age-matched subjects. INTERVENTIONS: Serum procalcitonin was determined by using an immunochemiluminescence assay, and C-reactive protein and leukocyte antigens were determined by using flow cytometry over 14 days in parallel with clinical data collection. MEASUREMENTS AND MAIN RESULTS: Despite a relative lymphopenia, absolute lymphocyte counts and CD4+/CD8+ T-cell ratio in septic patients were significantly elevated above normal. Particularly, CD4+ and CD8+ T-cell counts in nonsurvivors of sepsis were approximately twice as high as those of survivors. Significantly decreased monocytic HLA-DR expression was observed in both survivors and nonsurvivors at the onset of severe sepsis. Percentages of HLA-DR+ lymphocytes, however, were significantly increased during sepsis, especially in nonsurvivors. Whereas survivors of sepsis showed a continuous recovery of monocytic HLA-DR expression to >or=70% within 10 days, nonsurvivors were characterized by a second decrease in monocytic HLA-DR expression after day 7 or a permanent suppression (<40%). Peak of systemic inflammatory reaction, documented by maximum serum concentrations of procalcitonin and C-reactive protein, coincided with the nadir of monocytic HLA-DR expression. Moreover, procalcitonin and C-reactive protein as well as scores on the Acute Physiology and Chronic Health Evaluation II and Sepsis Organ Failure Assessment were inversely correlated with the monocytic HLA-DR expression. CONCLUSIONS: Decreases in monocytic HLA-DR expression occurred simultaneously with signs of hyperinflammation as early as the onset of severe sepsis and usually developed in opposite directions than inflammatory markers and sepsis severity scores.

Cardiac output measurement by pulse dye densitometry: a comparison with the Fick's principle and thermodilution method.

OBJECTIVE: To evaluate the agreement between cardiac output (CO) measurements obtained by a new dye dilution technique using pulse dye densitometry (PDD) and thermodilution (TD) and the direct Fick method (F). DESIGN AND SETTING: Prospective clinical study in a university hospital, cardiac surgery intensive care unit. PATIENTS: Fifty-eight cardiac surgery patients after admission to the intensive care unit (six were excluded due to a low pulse signal quality using the PDD method). MEASUREMENTS AND RESULTS: Mean CO was 5.3+/-1.8 l/min for PDD, 5.7+/-1.68 l/min for TD, and 6.16+/-1.66 l/min for F. There was a good correlation between PDD and TD ( r(2)=0.93) and between PDD and F ( r(2)=0.77). Bias and precision between PDD and TD were -0.39+/-0.5 l/min and -0.69+/-0.85 l/min between PDD and F. In general, PDD determined lower CO values than TD and F. Especially in patients with CO below 5 l/min PDD underestimated CO in comparison to TD and F (bias and precision: -0.51+/-0.40 l/min and -0.83+/-1.0 l/min). CONCLUSION: Comparison between PDD and TD showed good agreement for the normal to high CO range. However, agreement was poor in patients with low CO. In the latter patient group PDD showed relevant underestimation of CO compared to TD and F. Due to these limitations PDD cannot entirely replace the pulmonary artery catheter for CO determination.