Use and outcome of empiric echinocandins in critically ill patients.

BACKGROUND: Echinocandins are recommended as a first-line empiric treatment for fungal infections of patients in an intensive care unit (ICU) with critical illness. The primary aim of the study was to compare outcomes among ICU patients treated with empiric anidulafungin (ANI), caspofungin (CASPO), or micafungin (MICA). METHODS: A retrospective cohort study in a mixed adult ICU. Patient demographics, reason for ICU admission, ICU risk scores and organ support therapies were analyzed. Outcome parameters included ICU and hospital stay, 30-day mortality and 1-year mortality. RESULTS: Empiric echinocandin therapy was given to 367 patients (ANI; 73 patients, CASPO; 84 patients, and MICA; 210 patients) with a median duration of 3 days in an ICU. Patient median age was 60.7 years. As a first-line therapy, 52% of patients received fluconazole. Positive Candida cultures were found in the following samples: blood, 16 (4.4%); central line, 27 (7.4%); deep site, 92 (25.1%). Median ICU stay (ANI 6.4 days, CASPO 5.3 days, MICA 8.1 days), hospital stay (ANI 33 days, CASPO 30 days, MICA 30 days), 30-day mortality (ANI 27%, CASPO 32%, MICA 32%), and 1-year mortality (ANI 33%, CASPO 44%, MICA 45%) did not differ between the groups . The cost of antifungal therapy during the ICU period was similar in the three echinocandin groups (ANI; €1 872, CASPO; €1 799, and MICA; €1783). CONCLUSION: Our results show that ICU, hospital stay, and mortality (hospital, 30-day and 1-year) did not differ among patients with empiric anidulafungin, caspofungin, or micafungin treatment in a mixed adult ICU.

Colon epithelial injury in critically ill colectomized patients: aberration of tight junction proteins and Toll-like receptors.

BACKGROUND: Abnormal permeability and extensive epithelial injury are characteristic of colon wall damage complicating critical illness, such as sepsis, and associated with mortality. To assess mechanisms of such colon epithelial disruption, we studied expression of markers of innate immunity and intercellular junctions in patients with critical illness. METHODS: Emergency colectomy samples from 38 intensive care unit patients with sepsis, fulminant C. difficile colitis, or colon ischemia were studied. Expression of tight junction proteins (claudin­1, claudin­2, occludin) and Toll-like receptors (TLRs) (TLR2, TLR4, TLR5, and TLR9) was studied in samples representing histologically verified damaged segments of the colon, and compared with normal colon (N.=28). RESULTS: As compared with normal epithelium, histologically damaged samples showed decreased claudin­1 (P=0.002) expression. Expression of TLR2, TLR4, and TLR5 was similar in patients and controls, but TLR9 expression was up-regulated in the histologically damaged region (P=0.03). The expression of other markers (claudin­1, claudin­2, occludin, TLR2,TLR4, TLR5 and TLR9) did not differ between survivors and non-survivors. CONCLUSIONS: Down-regulation of claudin­1 and up-regulation of TLR9 suggest that epithelial barrier dysfunction and innate immunity activation are involved in the pathogenesis of colon epithelial injury in patients with critical illness.

Vitamin D deficiency at admission is not associated with 90-day mortality in patients with severe sepsis or septic shock: Observational FINNAKI cohort study.

Introduction Low levels of vitamin D have been associated with increased mortality in patients that are critically ill. This study explored whether vitamin D levels were associated with 90-day mortality in severe sepsis or septic shock. Methods Plasma vitamin D levels were measured on admission to the intensive care unit (ICU) in a prospective multicentre observational study. Results 610 patients with severe sepsis were included; of these, 178 (29%) had septic shock. Vitamin D deficiency (<50 nmol/L) was present in 333 (55%) patients. The 90-day mortality did not differ among patients with or without vitamin D deficiency (28.3% vs. 28.5%, p = 0.789). Diabetes was more common among patients deficient compared to those not deficient in vitamin D (30% vs. 18%, p < 0.001). Hospital-acquired infections at admission were more prevalent in patients with a vitamin D deficiency (31% vs. 16%, p < 0.001). A multivariable adjusted Cox regression model showed that low vitamin D levels could not predict 90-day mortality (<50 nmol/L: hazard ratio (HR) 0.99 (95% CI: 0.72-1.36), p > 0.9; and <25 nmol/L: HR 0.44 (95% CI: 0.22-0.87), p = 0.018). Conclusions Vitamin D deficiency detected upon ICU admission was not associated with 90-day mortality in patients with severe sepsis or septic shock. Key messages In severe sepsis and septic shock, a vitamin D deficiency upon ICU admission was not associated with increased mortality. Compared to patients with sufficient vitamin D, patients with deficient vitamin D more frequently exhibited diabetes, elevated C-reactive protein levels, and hospital-acquired infections upon ICU admission, and they more frequently developed acute kidney injury.

Variation in the use of renal replacement therapy in patients with septic shock: a substudy of the prospective multicenter observational FINNAKI study.

INTRODUCTION: Indications for renal replacement therapy (RRT) have not been generally standardized and vary among intensive care units (ICUs). We aimed to assess the proportion, indications, and modality of RRT, as well as the association between the proportion of RRT use and 90-day mortality in patients with septic shock in Finnish adult ICUs. METHODS: We identified patients with septic shock from the prospective observational multicenter FINNAKI study conducted between 1 September 2011 and 1 February 2012. We divided the ICUs into high-RRT and low-RRT ICUs according to the median of the proportion of RRT-treated patients with septic shock. Differences in indications, and modality of RRT between ICU groups were assessed. Finally, we performed an adjusted logistic regression analysis to evaluate the possible association of the ICU group (high vs. low-RRT) with 90-day mortality. RESULTS: Of the 726 patients with septic shock, 131 (18.0%, 95% CI 15.2 to 20.9%) were treated with RRT. The proportion of RRT-treated patients varied from 3% up to 36% (median 19%) among ICUs. High-RRT ICUs included nine ICUs (354 patients) and low-RRT ICUs eight ICUs (372 patients). In the high-RRT ICUs patients with septic shock were older (P = 0.04), had more cardiovascular (P <0.001) and renal failures (P = 0.003) on the first day in the ICU, were more often mechanically ventilated, and received higher maximum doses of norepinephrine (0.25 µg/kg/min vs. 0.18 µg/kg/min, P <0.001) than in the low-RRT ICUs. No significant differences in indications for or modality of RRT existed between the ICU groups. The crude 90-day mortality rate for patients with septic shock was 36.2% (95% CI 31.1 to 41.3%) in the high-RRT ICUs compared to 33.9% (95% CI 29.0 to 38.8%) in the low-RRT ICUs, P = 0.5. In an adjusted logistic regression analysis the ICU group (high-RRT or low-RRT ICUs) was not associated with 90-day mortality. CONCLUSIONS: Patients with septic shock in ICUs with a high proportion of RRT had more severe organ dysfunctions and received more organ-supportive treatments. Importantly, the ICU group (high-RRT or low-RRT group) was not associated with 90-day mortality.

Impact of preoperative organ failures on survival in intensive care unit patients with colectomy.

BACKGROUND: The present study aimed to evaluate the prognostic value of preoperative changes in sequential organ failure assessment (SOFA) score, daily norepinephrine (NE) dose, lactate, C-reactive protein, and white blood cell count among patients with colectomy in the intensive care unit (ICU). METHODS: We performed a retrospective analysis of 77 colectomized patients (30 female, 47 male) who were treated in a single tertiary-level mixed ICU during 2000-2009. RESULTS: The underlying conditions leading to colectomy included sepsis (31 patients), cardiovascular operations (21 patients), and fulminant Clostridium difficile colitis (25 patients). The 28-day mortality was 53.3 % (41/77). Nonsurvivors had significantly higher median values than survivors (p < 0.05) for the following parameters: admission SOFA [10.0 (25th-75th percentile 8.0-13.0) vs. 9.0 (6.5-10.0)], highest SOFA [14.0 (12.0-16.0) vs. 12.5 (9.5-14.5)], operative day lactate level (6.3 vs. 2.2 mmol/L), and NE dose (16.8 vs. 9.3 total mg/day). During the last three preoperative days, significant increases were observed in total SOFA score (p < 0.001) and in cardiovascular (p < 0.001), coagulation (p = 0.017), renal (p < 0.01), and respiratory (p < 0.001) SOFA subscores, without statistically significant differences between nonsurvivors and survivors. Increasing Glasgow Coma Scale score, preoperative lactate level, and NE dose were significantly associated with mortality. CONCLUSIONS: It should be prospectively studied whether preoperatively increasing lactate level and NE dose are surrogate markers for early laparotomy among ICU patents with colitis.

Incidence, risk factors and 90-day mortality of patients with acute kidney injury in Finnish intensive care units: the FINNAKI study.

PURPOSE: We aimed to determine the incidence, risk factors and outcome of acute kidney injury (AKI) in Finnish ICUs. METHODS: This prospective, observational, multi-centre study comprised adult emergency admissions and elective patients whose stay exceeded 24 h during a 5-month period in 17 Finnish ICUs. We defined AKI first by the Acute Kidney Injury Network (AKIN) criteria supplemented with a baseline creatinine and second with the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. We screened the patients' AKI status and risk factors for up to 5 days. RESULTS: We included 2,901 patients. The incidence (95 % confidence interval) of AKI was 39.3 % (37.5-41.1 %). The incidence was 17.2 % (15.8-18.6 %) for stage 1, 8.0 % (7.0-9.0 %) for stage 2 and 14.1 % (12.8-15.4 %) for stage 3 AKI. Of the 2,901 patients 296 [10.2 % (9.1-11.3 %)] received renal replacement therapy. We received an identical classification with the new KDIGO criteria. The population-based incidence (95 % CI) of ICU-treated AKI was 746 (717-774) per million population per year (reference population: 3,671,143, i.e. 85 % of the Finnish adult population). In logistic regression, pre-ICU hypovolaemia, diuretics, colloids and chronic kidney disease were independent risk factors for AKI. Hospital mortality (95 % CI) for AKI patients was 25.6 % (23.0-28.2 %) and the 90-day mortality for AKI patients was 33.7 % (30.9-36.5 %). All AKIN stages were independently associated with 90-day mortality. CONCLUSIONS: The incidence of AKI in the critically ill in Finland was comparable to previous large multi-centre ICU studies. Hospital mortality (26 %) in AKI patients appeared comparable to or lower than in other studies.

Colectomy in intensive care patients: operative findings and outcomes.

BACKGROUND: With a critical illness, intestinal complications are associated with high morbidity and mortality. METHODS: Operative findings and outcomes of 77 intensive care unit (ICU) patients treated with colectomy are described. RESULTS: Three conditions led to colectomy: sepsis (S group; n = 31), fulminant Clostridium difficile colitis (Cl group; n = 25), and cardiovascular surgery (CV group; n = 21). The median Acute Physiology and Chronic Health score was >25 in all groups. Thickening and distension of the colon was more frequent in the Cl group (p = 0.001), and ischemia was more frequent in the S and CV groups (p < 0.001). Widespread necrosis was more frequent in the CV patients (p = 0.001). The kappa value for ischemic operative findings and histologic necrosis was 0.64 (95 % confidence interval 0.49-0.79). Hospital mortality was 35 % without multiple organ failure (MOF) (n = 31) and 74 % with MOF (n = 46) (p < 0.001). Overall, 38 % were alive at the 1-year follow-up. CONCLUSIONS: Although colectomy in ICU patients is associated with high hospital mortality, patients who survive beyond their hospital stay have a good 1-year outcome.

Fluid overload is associated with an increased risk for 90-day mortality in critically ill patients with renal replacement therapy: data from the prospective FINNAKI study.

INTRODUCTION: Positive fluid balance has been associated with an increased risk for mortality in critically ill patients with acute kidney injury with or without renal replacement therapy (RRT). Data on fluid accumulation prior to RRT initiation and mortality are limited. We aimed to study the association between fluid accumulation at RRT initiation and 90-day mortality. METHODS: We conducted a prospective, multicenter, observational cohort study in 17 Finnish intensive care units (ICUs) during a five-month period. We collected data on patient characteristics, RRT timing, and parameters at RRT initiation. We studied the association of parameters at RRT initiation, including fluid overload (defined as cumulative fluid accumulation > 10% of baseline weight) with 90-day mortality. RESULTS: We included 296 RRT-treated critically ill patients. Of 283 patients with complete data on fluid balance, 76 (26.9%) patients had fluid overload. The median (interquartile range) time from ICU admission to RRT initiation was 14 (3.3 to 41.5) hours. The 90-day mortality rate of the whole cohort was 116 of 296 (39.2%; 95% confidence interval 38.6 to 39.8%). The crude 90-day mortality of patients with or without fluid overload was 45 of 76 (59.2%) vs. 65 of 207 (31.4%), P < 0.001. In logistic regression, fluid overload was associated with an increased risk for 90-day mortality (odds ratio 2.6) after adjusting for disease severity, time of RRT initiation, initial RRT modality, and sepsis. Of the 168 survivors with data on RRT use at 90 days, 34 (18.9%, 95% CI 13.2 to 24.6%) were still dependent on RRT. CONCLUSIONS: Patients with fluid overload at RRT initiation had twice as high crude 90-day mortality compared to those without. Fluid overload was associated with increased risk for 90-day mortality even after adjustments.

Risk factors for prolonged intensive care unit stay and hospital mortality in acute drug-poisoned patients: an evaluation of the physiologic and laboratory parameters on admission.

BACKGROUND: The share of patients receiving intensive care treatment because of acute drug poisoning is 2% to 14% of all patients receiving intensive care. The outcome is mainly good and the length of intensive care is usually less than 2 days. Our aim was to recognize the risks for prolonged intensive care and hospital mortality using admission Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scoring in acute drug-poisoned patients. METHODS: A national, prospectively collected intensive care unit (ICU) data registry was used for analysis. Data from 28 ICUs in university and secondary nonteaching hospitals from 1998 to 2004 were available. RESULTS: There were 255 admissions because of acute drug poisoning, which represented 4.5% of all admissions. The mean length of the ICU stay was 32.1 hours. Of the patients, 11.5% had a prolonged ICU stay (>48 hours). Hospital mortality was 2.3%. The mean Acute Physiology and Chronic Health Evaluation II score was 14.4 (SD, 8.1) and the mean Sequential Organ Failure Assessment score was 4.8 (SD, 3.0). The mean Glasgow Coma Scale score on admission was 9.7 (SD, 4.7). In the multivariate analysis, the highest odds ratios for prolonged ICU stay were respiratory failure, lowered platelet count, and renal dysfunction. In the multivariate analysis, the highest odds ratios for hospital mortality were respiratory failure, renal failure, and hypotension. CONCLUSIONS: In acute intoxication, respiratory and renal dysfunction and failure are risk factors for poor outcome.

Matrix-metalloproteinase-2, -8 and -9 in serum and skin blister fluid in patients with severe sepsis.

INTRODUCTION: Matrix metalloproteinases (MMPs) have various roles in inflammatory states. They seem to be able to modulate endothelial barriers and regulate the activity of chemokines and cytokines. The timely development of the levels during severe sepsis and thereafter have not been investigated. In addition it was of interest to study alterations of MMP-levels in intact skin, as the skin is the largest barrier against external pathogens and MMPs have not been studied at organ level in human sepsis. The aim of this study was to investigate the timely development of serum and skin MMP-2, -8 and -9 levels in human severe sepsis and their association with disease severity and mortality. METHODS: Forty-four patients with severe sepsis and fifteen healthy controls were included in this prospective longitudinal study. The amounts of MMP-2, -8 and -9 were analyzed from serum at days 1, 4, 6, 8, and 10, and from skin suction blister fluid at days 1 and 5 from the beginning of severe sepsis. Additionally, samples from the survivors were obtained after three and six months. RESULTS: The levels of MMP-2 and -8 were up-regulated in severe sepsis in comparison to healthy controls in skin blister fluid and serum. Compared to the controls MMP-9 levels were lower in sepsis from the fourth day on in serum and both the first and fifth day in skin blister fluid. Active forms of MMP-2 and -9 were present only in severe sepsis. The non-survivors had higher pro- and active MMP-2 levels than the survivors in skin blister fluid samples. Furthermore, MMP-2 levels were more pronounced in blister fluid and serum samples in patients with more severe organ failures. In the survivors at 3 and 6 month follow-up the MMP levels had returned to normal. CONCLUSIONS: MMP-2 and -8 are elevated in serum and blister fluid in severe sepsis, implying that they may play a significant role in the pathogenesis of severe sepsis and organ dysfunctions. Active forms of MMP-2 and 9 were only present in patients with severe sepsis, and higher MMP-2 levels in skin blister and serum were associated with more severe organ dysfunctions.

Epidermal wound healing in severe sepsis and septic shock in humans.

INTRODUCTION: The effect of sepsis on epidermal wound healing has not been previously studied. It was hypothesised that epidermal wound healing is disturbed in severe sepsis. METHODS: Blister wounds were induced in 35 patients with severe sepsis and in 15 healthy controls. The healing of the wounds was followed up by measuring transepidermal water loss and blood flow in the wound, reflecting the restoration of the epidermal barrier function and inflammation, respectively. The first set of suction blisters (early wound) was made within 48 hours of the first sepsis-induced organ failure and the second set (late wound) four days after the first wound. In addition, measurements were made on the intact skin. RESULTS: The average age of the whole study population was 62 years (standard deviation [SD] 12). The mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score on admission was 25 (SD 8). The two most common causes of infections were peritonitis and pneumonia. Sixty-six percent of the patients developed multiple organ failure. The decrease in water evaporation from the wound during the first four days was lower in septic patients than in the control subjects (56 g/m2 per hour versus 124 g/m2 per hour, P = 0.004). On the fourth day, septic patients had significantly higher blood flow in the wound compared with the control subjects (septic patients 110 units versus control subjects 47 units, P = 0.001). No difference in transepidermal water loss from the intact skin was found between septic patients and controls. Septic patients had higher blood flow in the intact skin on the fourth and on the eighth day of study compared with the controls. CONCLUSIONS: The restoration of the epidermal barrier function is delayed and wound blood flow is increased in patients with severe sepsis.

Cellular turnover and expression of hypoxic-inducible factor in acute acalculous and calculous cholecystitis.

INTRODUCTION: Epithelial corrective and destructive mechanisms have not been studied in inflammatory gallbladder disease. METHODS: Epithelial apoptosis, cell proliferation and expression of hypoxia-inducible factor (HIF)-1alpha were compared in gallbladders from patients with acute acalculous cholecystitis (AAC; n = 30) and acute calculous cholecystitis (ACC; n = 21), and from patients undergoing surgery for other reasons (normal gallbladders; n = 9), which were removed during open cholecystectomy. The immunohistochemical stains included antibodies to Ki-67 (proliferation), M30 (apoptosis) and HIF-1alpha. Proliferation and apoptosis were expressed as percentages of positive cells. HIF-1alpha expression was expressed as absent, weak, or strong. RESULTS: Apoptosis (median [25th to 75th percentile]) was significantly increased in AAC (1.31% [0.75% to 1.8%], P < 0.001) and ACC (1.10% [0.63% to 1.64%], P = 0.001), compared with control samples (0.20% [0.07% to 0.45%]. The proliferation rate was significantly increased in AAC (8.0% [4.0% to 17.0%], P < 0.001) and ACC (14% [7.5% to 26.5%], P = 0.001) compared with control samples (1.0% [1.0% to 3.0%]). Strong HIF-1alpha staining was observed in 57% of AAC, in 100% of ACC and in 44% of control specimens (P < 0.001). Intense HIF-1alpha expression was associated with increased cell proliferation (P = 0.002). CONCLUSION: Cell proliferation and apoptosis were increased in AAC and ACC, as compared with normal gallbladders. Expression of HIF-1alpha was lower in AAC than in ACC.

Tight junction proteins in gallbladder epithelium: different expression in acute acalculous and calculous cholecystitis.

There is a paucity of information of tight junction (TJ) proteins in gallbladder epithelium, and disturbances in the structure of these proteins may play a role in the pathogenesis of acute acalculous cholecystitis (AAC) and acute calculous cholecystitis (ACC). Using immunohistochemistry, we investigated the expression of TJ proteins claudin-1, -2, -3, and -4, occludin, zonula occludens (ZO-1), and E-cadherin in 9 normal gallbladders, 30 gallbladders with AAC, and 21 gallbladders with ACC. The number of positive epithelial and endothelial cells and the intensity of the immunoreaction were determined. Membrane-bound and cytoplasmic immunoreactivities were separately assessed. We found that TJ proteins were uniformly expressed in normal gallbladder epithelium, with the exception of claudin-2, which was present in less than half of the cells. In AAC, expression of cytoplasmic occludin and claudin-1 were decreased, as compared with normal gallbladder. In ACC, expression of claudin-2 was increased, and expression of claudin-1, -3, and -4, occludin, and ZO-1 were decreased, as compared with normal gallbladder or AAC. We conclude that there are significant differences in expression of TJ proteins in AAC and ACC, supporting the idea that AAC represents a manifestation of systemic inflammatory disease, whereas ACC is a local inflammatory and often infectious disease.

Validation of the new Intensive Care Nursing Scoring System (ICNSS).

OBJECTIVES: To validate a new Intensive Care Nursing Scoring System (ICNSS). DESIGN: Retrospective data collection. SETTING: Adult 19-bed intensive care unit (ICU) in a tertiary care university hospital. PATIENTS: A total of 1,538 patient records of which 30 documents were included in the validation. MEASUREMENTS AND RESULTS: Data included admission scores of the Acute Physiology and Chronic Health Evaluation II (APACHE II) and the Simplified Acute Physiology Scores II (SAPS II), daily Therapeutic Intervention Scores (TISS) and ICNSS scores. Data were compared using Spearman's correlation, t-test and chi-square test. Receiver operating characteristics (ROC) curve analysis was used to assess the ability of ICNSS and TISS to predict mortality. Intra-class correlation, percentage agreement and kappa statistics were used to test the validity of given scores. Nursing workload assessment using ICNSS showed that medical and emergency-operated patients caused a greater nursing workload than electively operated patients (p<0.001). Six variables of the sub-scale that described vital function nursing accounted for 27.4% of the variation of SAPS II and for 37% of the variation of APACHE II. The ICNSS sub-scale of vital function nursing accounted for a ROC area of 0.91. In the validity of the given ICNSS scores, kappa was 0.81 and weighted kappa 0.82. CONCLUSIONS: Nursing workload varied between the different admission types. ICNSS explained a similar percentage of the variation of the admission scores of APACHE II and SAPSS II as TISS and discriminated between non-survivors and survivors. ICNSS is a suitable nursing workload instrument to be used with the TISS score.