Pharmacokinetics of Caspofungin in Critically Ill Patients in Relation to Liver Dysfunction: Differential Impact of Plasma Albumin and Bilirubin Levels.

Caspofungin has a liver-dependent metabolism. Reduction of the dose is recommended based on Child-Pugh (C-P) score. In critically ill patients, drug pharmacokinetics (PK) may be altered. The aim of this study was to investigate the prevalence of abnormal liver function tests, increased C-P scores, their effects on caspofungin PK, and whether pharmacokinetic-pharmacodynamic (PK/PD) targets were attained in patients with suspected candidiasis. Intensive care unit patients receiving caspofungin were prospectively included. PK parameters were determined on days 2, 5, and 10, and their correlations to the individual liver function tests and the C-P score were analyzed. Forty-six patients were included with C-P class A (n = 5), B (n = 40), and C (n = 1). On day 5 (steady state), the median and interquartile range for area under the curve from 0 to 24 h (AUC0-24), clearance (CL), and central volume of distribution (V1) were 57.8 (51.6 to 69.8) mg·h/liter, 0.88 (0.78 to 1.04) liters/h, and 11.9 (9.6 to 13.1) liters, respectively. The C-P score did not correlate with AUC0-24 (r = 0.03; P = 0.84), CL (r = -0.07; P = 0.68), or V1 (r = 0.19; P = 0.26), but there was a bilirubin-driven negative correlation with the elimination rate constant (r = -0.46; P = 0.004). Hypoalbuminemia correlated with low AUC0-24 (r = 0.45; P = 0.005) and was associated with higher clearance (r = -0.31; P = 0.062) and somewhat higher V1 (r = -0.15; P = 0.37), resulting in a negative correlation with the elimination rate constant (r = -0.34; P = 0.042). For Candida strains with minimal inhibitory concentrations of ≥0.064 µg/ml, PK/PD targets were not attained in all patients. The caspofungin dose should not be reduced in critically ill patients in the absence of cirrhosis, and we advise against the use of the C-P score in patients with trauma- or sepsis-induced liver injury.

Neurointensive care of patients with severe community-acquired meningitis.

BACKGROUND: Reports about neurointensive care of severe community-acquired meningitis are few. The aims of this retrospective study were to review the acute clinical course, management and outcome in a series of bacterial meningitis patients receiving neurointensive care. METHODS: Thirty patients (median age 51, range 1-81) admitted from a population of 2 million people during 7 years were studied. The neurointensive care protocol included escalated stepwise treatment with mild hyperventilation, cerebrospinal fluid (CSF) drainage, continuous thiopentotal infusion and decompressive craniectomy. Clinical outcome was assessed using the Glasgow outcome scale. RESULTS: Twenty-eight patients did not respond to commands on arrival, five were non-reacting and five had dilated pupils. Twenty-two patients had positive CSF cultures: Streptococcus pneumoniae (n=18), Neisseria meningitidis (n=2), ß-streptococcus group A (n=1) and Staphylococcus aureus (n=1). Thirty-five patients were mechanically ventilated. Intracranial pressure (ICP) was monitored in 28 patients (intraventricular catheter=26, intracerebral transducers=2). CSF was drained in 15 patients. Three patients received thiopentothal. Increased ICP (>20 mmHg) was observed in 7/26 patients with available ICP data. Six patients died during neurointensive care: total brain infarction (n=4), cardiac arrest (n=1) and treatment withdrawal (n=1). Seven patients died after discharge, three due to meningitis complications. At follow-up, 14 patients showed good recovery, six moderate disability, two severe disability and 13 were dead. CONCLUSION: Patients judged to have severe meningitis should be admitted to neurointensive care units without delay for ICP monitoring and management according to modern neurointensive care principles.

Diagnosis-dependent misclassification of infections using administrative data variably affected incidence and mortality estimates in ICU patients.

OBJECTIVE: To determine the accuracy of hospital discharge diagnoses in identifying severe infections among intensive care unit (ICU) patients, and estimate the impact of misclassification on incidence and 1-year mortality. STUDY DESIGN AND SETTING: Sepsis, pneumonia, and central nervous system (CNS) infections among 7,615 ICU admissions were identified using ICD-9 and ICD-10 diagnoses from the Swedish hospital discharge register (HDR). Sensitivity, specificity, and likelihood ratios were calculated using ICU database diagnoses as reference standard, with inclusion in sepsis trials (IST) as secondary reference for sepsis. RESULTS: CNS infections were accurately captured (sensitivity 95.4% [confidence interval (CI)=86.8-100] and specificity 99.6% [CI=99.4-99.8]). Community-acquired sepsis (sensitivity 51.1% [CI=41.0-61.2] and specificity 99.4% [CI=99.2-99.6]) and primary pneumonia (sensitivity 38.2% [CI=31.2-45.2] and specificity 98.6% [CI=98.2-99.0]) were more accurately detected than sepsis and pneumonia in general. One-year mortality was accurately estimated for primary pneumonia but underestimated for community-acquired sepsis. However, there were only small differences in sensitivity and specificity between HDR and ICU data in the ability to identify IST. ICD-9 appeared more accurate for sepsis, whereas ICD-10 was more accurate for pneumonia. CONCLUSION: Accuracy of hospital discharge diagnoses varied depending on diagnosis and case definition. The pattern of misclassification makes estimates of relative risk more accurate than estimates of absolute risk.

C5a, interleukin-8 and tumour necrosis factor-alpha-induced changes in granulocyte and monocyte expression of complement receptors in whole blood and on isolated leukocytes.

Treatments targeting complement receptors have been demonstrated to improve outcome in experimental sepsis. The regulation of the complement receptors in sepsis is not clear. Lipopolysaccharide (LPS) stimulation of granulocytes ex vivo has been shown to reduce C5a receptor (CD88) expression and to increase CD35 and CD11b/CD18 expressions in whole blood but not on isolated cells, indicating an indirect effect mediated via factors in the blood. With the aim to study whether these effects could be attributed to C5a, tumour necrosis factor (TNF)-alpha and interleukin (IL)-8, whole blood or isolated granulocytes and monocytes from healthy individuals were investigated. After incubation with C5a in a dose range of 1 x 10(-9)-1 x 10(-7) mol/l, and TNF-alpha and IL-8 at doses of 1-100 ng/ml, the expressions of the complement receptors CD88, CD35, CD11b/CD18 were analysed by flow cytometry. Incubation with C5a reduced granulocyte CD88 expression by 44+/-6.9% and 82+/-4.2%, whereas monocyte CD88 expression decreased by 21+/-4.0 and 30+/-17% (whole blood and isolated cells). IL-8 and TNF-alpha incubation of granulocytes induced similar results. Granulocyte CD35 expression was significantly increased by 367, 175 and 336% by C5a, TNF-alpha, IL-8, respectively; CD11b expression was similarly increased. Consistent with findings in septic patients and after LPS incubation, it is concluded that all stimuli reduced granulocyte CD88 expression, whereas CD35 and CD11b were increased.

Differential expression of the C5a receptor and complement receptors 1 and 3 after LPS stimulation of neutrophils and monocytes.

Animal experiments recently suggested that administration of anti-C5a, anti-C5a receptor or soluble complement receptor type-1 may be of value in the treatment of septic shock. Because results regarding C5a receptor expression (C5a-R, CD-88) have been found to differ between septic animals and patients, the aim of this study was to investigate the neutrophil and monocyte receptor expression of CD-88 and complement receptor-1 (CR-1, CD-35) after stimulation with lipopolysaccharide (LPS) ex vivo. Whole blood or isolated neutrophils and monocytes from healthy people were incubated with LPS in a dose range of 0.1-1000 ng/ml. The expressions of CD-88 and CD-35 were analysed by means of flow cytometry. For comparison, the expressions of complement receptor-3 (CR-3, CD-11b/CD-18), Fc-gamma receptor type-I (CD-64) and CEACAM-8 (CD-66b) were also investigated. In whole blood, CD-88 expression on neutrophils was reduced (P < 0.05). The expressions of CD-35 and CD-11b were increased both on neutrophils (P < 0.001; P < 0.05) and on monocytes (P < 0.001; P < 0.001). No effect was observed on isolated cells. In agreement with the findings in septic patients, LPS reduced the neutrophil C5a-R expression, whereas the expressions of CR-1 and CR-3 were increased. The effects of LPS were indirect and were mediated via factors in the blood. The clinical significance of this is not known, but may be associated with decreased chemotaxis.