Population pharmacokinetics and probability of target attainment in patients with sepsis under renal replacement therapy receiving continuous infusion of meropenem: Sustained low-efficiency dialysis and continuous veno-venous haemodialysis.

AIMS: To describe the population pharmacokinetics (PK) and probability of target attainment (PTA) of continuous infusion (CI) of meropenem in septic patients receiving renal replacement therapy (RRT). METHODS: Fifteen patients without RRT, 13 patients receiving sustained low-efficiency dialysis and 12 patients receiving continuous veno-venous haemodialysis were included. Population PK analysis with Monte Carlo simulations for different dosing regimens was performed. For minimum inhibitory concentration 2 mg/L was chosen. The target was set as 50% time ≥4× minimum inhibitory concentration. RESULTS: The PK of meropenem was best described by a 1-compartment model with linear elimination. Serum creatinine, residual diuresis and time on RRT, with no difference between sustained low-efficiency dialysis and continuous veno-venous haemodialysis, were found to be significant covariates affecting clearance, explaining >20% of the clearance between subject variability. PTA analysis showed that in patients with RRT, 2 g/24 h, meropenem CI achieved a PTA of 95%. In patients without RRT, the target was achieved with 3 g/24 h CI or prolonged infusion of 1 g meropenem over 8 hours but not with bolus application of 1 g meropenem for 8 hours. Only 2 patients (both without RRT) had meropenem concentrations below the target level. However, approximately half of the patients with RRT receiving CI 3 g/24 h meropenem had toxic concentrations. CONCLUSION: We found relevant PK variability for meropenem CI in septic patients with or without RRT, leading to a substantial risk for overdosing in patients with RRT. This finding highlights the strong demand for personalized dosing in critically ill patients.

Endogenous vasopressin and copeptin response in multiple trauma patients.

Endogenous arginine vasopressin (AVP) levels in multiple trauma patients are unknown. Arginine vasopressin is considered to play an important role in severe hemorrhage. In this prospective study, 87 multiple trauma patients (Injury Severity Score >15) and 50 healthy volunteers were enrolled. On admission to the emergency department (ED), demographic, clinical, and laboratory data were documented, and blood was sampled for determination of AVP (radioimmunosassay) and copeptin, a stable fragment of the AVP precursor (immunoluminometric assay). In patients requiring intensive care unit (ICU) therapy, blood and data sampling were repeated at 4, 6, and 24 h after ED admission. Linear logistic and mixed-effects regression analyses were used for statistical analysis. On ED admission, AVP plasma concentrations (43.2 +/- 84.9 pM) were significantly increased when compared with controls (0.92 +/- 0.44 pM, P < 0.001). Plethysmographic oxygen saturation was the only parameter independently associated with AVP (regression coefficient, -0.126; 95% confidence interval, -0.237 to -0.014; P = 0.03). No correlation was observed between AVP and survival (P = 0.62), hemodynamic variables (systolic arterial pressure, P = 0.24; MAP, P = 0.59; diastolic arterial pressure, P = 0.74; central venous pressure, P = 0.36), or brain trauma (P = 0.46). In ICU patients, AVP decreased during the first 24 h (P < 0.001) and was independently associated with heart rate (P = 0.02) and blood glucose (P = 0.009). Copeptin concentrations were correlated with AVP (r2 = 0.718, P < 0.001). In conclusion, AVP was significantly increased in multiple trauma patients and seems to be an integral part of the neuroendocrine response to severe injury. In ICU patients, AVP decreased to moderately elevated levels within 24 h after ED admission.

A novel questionnaire to measure staff perception of end-of-life decision making in the intensive care unit--development and psychometric testing.

PURPOSE: The aim of this study was to create a questionnaire that measures barriers and facilitators of effective end-of-life (EOL) decision making and communication and associated stress as perceived by intensive care unit (ICU) staff. METHODS: The questionnaire was developed on the basis of a theoretical framework and discussion with ICU staff. It was pretested among 15 ICU nurses and physicians. A field test was conducted in 4 interdisciplinary ICUs of one university hospital Descriptive item analysis, exploratory factor analysis, and reliability and validity analysis were performed. RESULTS: Overall, 174 of 284 ICU staff participated in the field test (61% response). Factor analysis indicated a 7-factor solution: (1) collaboration in the EOL context, (2) role clarity in the EOL context, (3) work-related interruptions of communication with families, (4) emotional support, (5) stress by involvement in EOL decision making and communication with families, (6) stress by work overload, and (7) taking initiative toward EOL decision making. Internal consistency of the scales was acceptable (range, 0.69-0.85). Construct validity was shown by relationships of the scales to several constructs, for example, satisfaction with EOL decision making and emotional exhaustion. Overall, 26 of 31 expected relationships achieved significance. CONCLUSIONS: The new questionnaire meets psychometric criteria of reliability and validity and promises to be a useful quality measure of EOL decision making in the ICU.

Are written advance directives helpful to guide end-of-life therapy in the intensive care unit? A retrospective matched-cohort study.

PURPOSE: The purpose of the study was to determine whether treatment preferences in patients' advance directives (ADs) are associated with life-supporting treatments received during end-of-life care in the intensive care unit (ICU). MATERIAL AND METHODS: This is a retrospective cohort study, including patients who died in 4 ICUs of a university hospital in Germany. Patients with ADs were matched with 2 patients each without ADs using propensity scores. RESULTS: Sixty-four (13%) of 477 patients had ADs, written a median of 109 weeks before admission. Five categories of applicability conditions were identified, most of them difficult to interpret in the ICU (eg, "advanced brain impairment" or "imminent death"). Advance directives contained a number of treatment refusals. Specifically, 63 of 64 refused "life-sustaining measures." Compared to patients without ADs, patients with ADs were less likely to receive cardiopulmonary resuscitation (9% vs 23%, P = .029) and more likely to have do-not-resuscitate orders (77% vs 56%, P = .007). Therapy-limiting decisions and ICU length of stay did not differ between those with or without ADs. CONCLUSIONS: Patients with ADs are less likely to receive cardiopulmonary resuscitation but otherwise receive similar life-sustaining treatments compared to matched patients without ADs. More research is needed to explore reasons for potential noncompliance with patient preferences.

Family satisfaction in the intensive care unit: a quantitative and qualitative analysis.

PURPOSE: To assess family satisfaction in the intensive care unit (ICU) and areas for improvement using quantitative and qualitative analyses. METHODS: Prospective cohort study performed in four (mixed surgical, neurological, and cardiological) intensive care units of a university hospital in Germany, using a translated and validated version of the Family Satisfaction in the ICU (FS-ICU) questionnaire, with questions answerable on a rating scale and three open-ended questions about strengths and weaknesses. Quantitative analysis was performed to identify items with low performance and high importance. For qualitative analysis, comments were coded and analyzed to identify important themes. Patient-related data were obtained from an electronic patient data management system. RESULTS: Participants were 215 family members visiting adult intensive care patients with length of stay over 48 h. Response rate was 28 %. Respondents were highly satisfied; summary scores were 78.3 ± 14.3 [mean ± standard deviation (SD)] on a scale of 0 (poor) to 100 (excellent). Regression analysis failed to identify association with patient- or family-related factors. The following themes for possible improvement emerged from both quantitative and qualitative analyses: patient agitation-consistency, clarity and completeness of information-emotional support-respect and compassion towards families. Families were also dissatisfied with the waiting room, ICU atmosphere, and amenities for visiting relatives. CONCLUSIONS: Families report high satisfaction with intensive care. Nevertheless, there is room for improvement, in particular regarding how ICU staff communicate with families and provide emotional support.

The exclusive use of coagulation factor concentrates enables reversal of coagulopathy and decreases transfusion rates in patients with major blunt trauma.

BACKGROUND: FFP and coagulation factor concentrates are used to correct trauma-induced coagulopathy (TIC). However, data on coagulation profiles investigating effects of therapy are scarce. METHODS: This is an analysis of 144 patients with major blunt trauma ((ISS)≥15), who were enrolled in a prospective cohort study investigating characteristics and treatment of TIC. Patients who received fibrinogen concentrate and/or prothrombin complex concentrate alone (CF Group) were compared with those additionally receiving FFP transfusions (FFP Group). RESULTS: Sixty-six patients exclusively received CF, while 78 patients additionally received FFP. Overall, patients were comparable regarding age, gender and ISS (CF Group, ISS 37 (29, 50); FFP Group ISS 38 (33, 55), p=0.28). Patients treated with CF alone showed sufficient haemostasis and received significantly fewer units of red blood cells (RBC) and platelets than did those also receiving FFP [(RBC 2(0, 4) U vs. 9 (5, 12) U; platelets 0 (0, 0) U vs. 1 (0, 2) U, p<0.001)]. In addition, fewer patients in the CF Group developed multiorgan failure (MOF) (18.2% vs. 37.2%, p=0.01) or sepsis (16.9% vs. 35.9%, p=0.014) than in the FFP Group. Propensity score-matching (n=28 pairs) used to reduce the impact of treatment selection confirmed that additional FFP administration showed no benefit in restoring haemostasis, but was associated with significantly higher transfusion rates for RBC and platelets. CONCLUSION: The use of CF alone effectively corrected coagulopathy in patients with severe blunt trauma and concomitantly decreased exposure to allogeneic transfusion, which may translate into improved outcome.

The impact of fresh frozen plasma vs coagulation factor concentrates on morbidity and mortality in trauma-associated haemorrhage and massive transfusion.

INTRODUCTION: Clinical observations together with recent research highlighted the role of coagulopathy in acute trauma care and early aggressive treatment has been shown to reduce mortality. METHODS: Datasets from severely injured and bleeding patients with established coagulopathy upon emergency room (ER) arrival from two retrospective trauma databases, (i) TR-DGU (Germany) and (ii) Innsbruck Trauma Databank/ITB (Austria), that had received two different strategies of coagulopathy management during initial resuscitation, (i) fresh frozen plasma (FFP) without coagulation factor concentrates, and (ii) coagulation factor concentrates (fibrinogen and/or prothrombin complex concentrates) without FFP, were compared for morbidity, mortality and transfusion requirements using a matched-pair analysis approach. RESULTS: There were no major differences in basic characteristics and physiological variables upon ER admission between the two cohorts that were matched. ITB patients had received substantially less packed red blood cell (pRBC) concentrates within the first 6h after admission (median 1.0 (IQR(25-75) 0-3) vs 7.5 (IQR(25-75) 4-12) units; p<0.005) and the first 24h as compared to TR-DGU patients (median 3 (IQR(25-75) 0-5) vs 12.5 (8-20) units; p<0.005). Overall mortality was comparable between both groups whilst the frequency for multi organ failure was significantly lower within the group that had received coagulation factor concentrates exclusively and no FFP during initial resuscitation (n=3 vs n=15; p=0.015). This translated into trends towards reduced days on ventilator whilst on ICU and shorter overall in-hospital length of stays (LOS). CONCLUSION: Although there was no difference in overall mortality between both groups, significant differences with regard to morbidity and need for allogenic transfusion provide a signal supporting the management of acute post-traumatic coagulopathy with coagulation factor concentrates rather than with traditional FFP transfusions. Prospective and randomised clinical trials with sufficient patient numbers based upon this strategy are advocated.