Lack of clinically evident signs of organ failure affects ED treatment of patients with severe sepsis

BACKGROUND: It is not known whether lack of recognition of organ failure explains the low compliance with the “Surviving Sepsis Campaign” (SSC) guidelines. We evaluated whether compliance was higher in emergency department (ED) sepsis patients with clinically recognizable signs of organ failure compared to patients with only laboratory signs of organ failure. METHODS: Three hundred twenty-three ED patients with severe sepsis and septic shock were prospectively included. Multivariable binary logistic regression was used to assess if clinical and biochemical signs of organ failure were associated with compliance to a SSC-based resuscitation bundle. In addition, two-way analysis of variance was used to investigate the relation between the predisposition, infection, response and organ failure (PIRO) score (3 groups: 1–7, 8–14, 15–24) as a measure of illness severity and time to antibiotics with disposition to ward or ICU as effect modifier. RESULTS: One hundred twenty-five of 323 included sepsis patients with new-onset organ failure were admitted to the ICU, and in all these patients the SSC resuscitation bundle was started. Respiratory difficulty, hypotension and altered mental status as clinically recognizable signs of organ failure were independent predictors of 100% compliance and not illness severity per se. Corrected ORs (95% CI) were 3.38 (1.08–10.64), 2.37 (1.07–5.23) and 4.18 (1.92–9.09), respectively. Septic ED patients with clinically evident organ failure were more often admitted to the ICU compared to a ward (125 ICU admissions, P < 0.05), which was associated with shorter time to antibiotics [ward: 127 (113–141) min; ICU 94 (80–108) min (P = 0.005)]. CONCLUSIONS: The presence of clinically evident compared to biochemical signs of organ failure was associated with increased compliance with a SSC-based resuscitation bundle and admission to the ICU, suggesting that recognition of severe sepsis is an important barrier for successful implementation of quality improvement programs for septic patients. In septic ED patients admitted to the ICU, the time to antibiotics was shorter compared to patients admitted to a normal ward

Identification of novel translational urinary biomarkers for acetaminophen-induced acute liver injury using proteomic profiling in mice

Contains fulltext : 108207.pdf (publisher's version ) (Open Access)Drug-induced liver injury (DILI) is the leading cause of acute liver failure. Currently, no adequate predictive biomarkers for DILI are available. This study describes a translational approach using proteomic profiling for the identification of urinary proteins related to acute liver injury induced by acetaminophen (APAP). Mice were given a single intraperitoneal dose of APAP (0-350 mg/kg bw) followed by 24 h urine collection. Doses of >/=275 mg/kg bw APAP resulted in hepatic centrilobular necrosis and significantly elevated plasma alanine aminotransferase (ALT) values (p<0.0001). Proteomic profiling resulted in the identification of 12 differentially excreted proteins in urine of mice with acute liver injury (p<0.001), including superoxide dismutase 1 (SOD1), carbonic anhydrase 3 (CA3) and calmodulin (CaM), as novel biomarkers for APAP-induced liver injury. Urinary levels of SOD1 and CA3 increased with rising plasma ALT levels, but urinary CaM was already present in mice treated with high dose of APAP without elevated plasma ALT levels. Importantly, we showed in human urine after APAP intoxication the presence of SOD1 and CA3, whereas both proteins were absent in control urine samples. Urinary concentrations of CaM were significantly increased and correlated well with plasma APAP concentrations (r = 0.97; p<0.0001) in human APAP intoxicants, who did not present with elevated plasma ALT levels. In conclusion, using this urinary proteomics approach we demonstrate CA3, SOD1 and, most importantly, CaM as potential human biomarkers for APAP-induced liver injury

Most frequent presented ICPC domains.

<p>Most frequent presented ICPC domains.</p

Detection of SOD1, CA3 and CaM in human urine samples.

<p>Presence of CA3 and SOD1 was assessed by Western blot in urine samples of masterpool control (I), severe APAP intoxication sample 1 (II) and 2 (III) and a positive control (IV) (panel A). Using an ELISA assay, the urinary concentration of CaM was correlated with plasma APAP concentrations using the Pearson correlation (r) test in patients with an APAP-intoxication, but without elevated plasma ALT values (B). The open data point represents the masterpool control urine sample. ALT: alanine aminotransferase; APAP acetaminophen; CA3: carbonic anhydrase 3; CaM: calmodulin; SOD1: superoxide dismutase 1.</p

Identification of CA3, SOD1 and CaM in mouse urine.

<p>Western blots show the relation between urinary SOD1 and CA3, and plasma ALT levels in individual mice (n = 13; panel A), of which urinary SOD1 intensity on Western blot was analyzed by linear regression analysis (B). Immunoprecipitation demonstrated the specific protein profile of CaM, i.e. the mass peak for CaM at 16.8 kDa (CaM^+H) and its double and triple charged form (CaM^+2H and CaM^+3H), in mouse urine after APAP treatment (C). ALT: alanine aminotransferase; APAP: acetaminophen; CA3: carbonic anhydrase 3; CaM: calmodulin; SOD1: superoxide distmutase 1.</p

Demographics acute DILI patients.

<p>Mean values for the APAP intoxicants are represented as mean ± SD.</p

Urinary protein profiles of APAP-induced liver injury in mice.

<p>Representative urine protein profiles of <i>m/z</i> values versus peak intensity illustrate an APAP dose-related increase in urinary protein excretion (A). ALT-dependent increases in protein peaks were observed in urine samples pretreated with WCX beads or C8 beads (B). The protein masses of 15.9 kDa and 16.8 kDa are indicated by (I) and (II), respectively. Double charged forms are indicated by (+2H). The correlation between the relative peak intensity of two representative urinary CA3 fragments (C & D), SOD1 (E), and CaM (F) and plasma ALT was determined using the Spearman's rank correlation coefficient (r) in mice with APAP dose ≥275 mg/kg body weight. ALT: alanine aminotransferase; APAP: acetaminophen; CA3: carbonic anhydrase 3; CaM: calmodulin; SOD1: superoxide dismutase 1; WCX: weak cation exchange.</p

Thromboprophylaxis after Knee Arthroscopy and Lower-Leg Casting

Background The use of thromboprophylaxis to prevent clinically apparent venous thromboembolism after knee arthroscopy or casting of the lower leg is disputed. We compared the incidence of symptomatic venous thromboembolism after these procedures between patients who received anticoagulant therapy and those who received no anticoagulant therapy. Methods We conducted two parallel, pragmatic, multicenter, randomized, controlled, open-label trials with blinded outcome evaluation: the POT-KAST trial, which included patients undergoing knee arthroscopy, and the POT-CAST trial, which included patients treated with casting of the lower leg. Patients were assigned to receive either a prophylactic dose of low-molecular-weight heparin (for the 8 days after arthroscopy in the POT-KAST trial or during the full period of immobilization due to casting in the POT-CAST trial) or no anticoagulant therapy. The primary outcomes were the cumulative incidences of symptomatic venous thromboembolism and major bleeding within 3 months after the procedure. Results In the POT-KAST trial, 1543 patients underwent randomization, of whom 1451 were included in the intention-to-treat population. Venous thromboembolism occurred in 5 of the 731 patients (0.7%) in the treatment group and in 3 of the 720 patients (0.4%) in the control group (relative risk, 1.6; 95% confidence interval [CI], 0.4 to 6.8; absolute difference in risk, 0.3 percentage points; 95% CI, -0.6 to 1.2). Major bleeding occurred in 1 patient (0.1%) in the treatment group and in 1 (0.1%) in the control group (absolute difference in risk, 0 percentage points; 95% CI, -0.6 to 0.7). In the POT-CAST trial, 1519 patients underwent randomization, of whom 1435 were included in the intention-to-treat population. Venous thromboembolism occurred in 10 of the 719 patients (1.4%) in the treatment group and in 13 of the 716 patients (1.8%) in the control group (relative risk, 0.8; 95% CI, 0.3 to 1.7; absolute difference in risk, -0.4 percentage points; 95% CI, -1.8 to 1.0). No major bleeding events occurred. In both trials, the most common adverse event was infection. Conclusions The results of our trials showed that prophylaxis with low-molecular-weight heparin for the 8 days after knee arthroscopy or during the full period of immobilization due to casting was not effective for the prevention of symptomatic venous thromboembolism. (Funded by the Netherlands Organization for Health Research and Development; POT-KAST and POT-CAST ClinicalTrials.gov numbers, NCT01542723 and NCT01542762 , respectively.)