The association between increasing fluid balance, acute kidney injury and mortality in patients with sepsis and septic shock: A retrospective single center audit.

PURPOSE: To determine whether a positive fluid balance is associated with AKI and mortality in sepsis and septic shock patients. METHODS: A retrospective chart review of 482 patients treated for sepsis or septic shock. Patients were stratified according to quartiles of cumulative fluid balance on days 1 and 3. Logistic models were built to explore the association between fluid balance, AKI, and ICU mortality. RESULTS: During the first days of ICU admission, fluid input did not differ between survivors and non-survivors, yet a significant difference in output resulted in a more positive fluid balance in non-survivors on day 1 (37.24 ± 31.98 ml/kg vs. 24.97 ± 23.76 ml/kg, p < 0.001) and day 3 (83.33 ± 70.86 ml/kg vs. 62.20 ± 45.90 ml/kg, P = 0.005). Using a logistic regression model, a positive fluid balance on day three was independently associated with higher ICU mortality (odds ratio 1.007 for every one ml/kg, P = 0038) and AKIN stage III (odds ratio 1.006 for every one ml/kg, p = 0.031). CONCLUSION: In patients with sepsis and septic shock, a more positive fluid balance is associated with an increased incidence of acute kidney injury and death after correction for possible confounders.

A case report: septic shock due to (tropical) pyomyositis and multiple metastatic embolisms caused by Panton Valentine Leukocidin-positive methicillin-sensitive staphylococcus aureus in a 12-year-old boy.

CASE REPORT: A 12-year-old boy, of Congolese roots and without medical history, first presented to our Emergency Department 3 days after blunt trauma of the left ankle. The boy represented on two more occasions in the next 3 days due to ongoing pain. On the last occasion he presented with severe hypoglycaemia. He was diagnosed with severe septic shock, secondary to subperiosteal abscess formation / osteomyelitis of the ankle. The patient was transferred to the paediatric intensive care unit where appropriate medical care was provided, including broad-spectrum antibiotic therapy, high dose vasopressor / inotropic support, surgical debridement of abscesses and below-knee amputation. PANTON VALENTINE LEUKOCIDIN TOXIN AND PYOMYOSITIS TROPICALIS: The causative organism was a methicillin-susceptible S. aureus, which upon further identification was a carrier of the PVL (Panton Valentine leukocidin) toxin. This pathogen is responsible for severe musculoskeletal infections. In children these infections are often associated with more severe clinical course requiring a higher need for surgical intervention and longer hospital stay.Tropical pyomyositis is a disease caused by Staphylococcus aureus, often seen in tropical countries, and classically presented with muscle abscesses. Young males between the ages of 10-40 years old are the most susceptible, and often present with a history of blunt trauma. Treatment generally requires a combination of an anti-staphylococcal agent, and an anti-toxic agent blocking bacterial protein-synthesis of PVL. Source control by surgical debridement also plays a major role in the treatment of PVL-infection. Despite agressive treatment, mortality still varies from 0.5% to 2%.

A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis.

OBJECTIVE: To evaluate whether TAK-242, a small-molecule inhibitor of Toll-like receptor-4-mediated signaling, suppresses cytokine levels and improves 28-day all-cause mortality rates in patients with severe sepsis. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: A total of 93 intensive care units worldwide. PATIENTS: A total of 274 patients with severe sepsis and shock or respiratory failure. INTERVENTIONS: Patients were randomly assigned to receive a 30-min loading dose followed by 96-hr infusions of placebo, TAK-242 1.2 mg/kg/day, or TAK-242 2.4 mg/kg/day. MEASUREMENTS AND MAIN RESULTS: The primary pharmacodynamic end point was change in serum interleukin-6 levels relative to baseline, with 28-day all-cause mortality rate the primary clinical end point. The trial was terminated because of a lack of effect of TAK-242 in suppressing serum interleukin-6 levels. A total of 274 subjects were randomly assigned and treated. Clinical parameters at baseline were balanced across the three groups. TAK-242 did not suppress interleukin-6 as measured by 0- to 96.5-hr area under the interleukin-6 concentration curve at either dose. Specifically, the area under the effect curve increased by 9% and 26.9% in the TAK-242 1.2 and 2.4 mg/kg/day groups, respectively, which was not statistically different from placebo (p = .63 and .15, respectively). The 28-day mortality rate was 24% in the placebo, 22% in the low-dose, and 17% in the high-dose group (p = .26 for placebo vs. high dose). A nonsignificant reduction in mortality rate was observed in a subset of patients with both shock and respiratory failure (placebo [n = 51], 33%, vs. high dose [n = 52], 19%, p = .10). Transient, dose-related increases in methemoglobin levels were observed with TAK-242 treatment in 30.1% of the patients. CONCLUSIONS: TAK-242 failed to suppress cytokine levels in patients with sepsis and shock or respiratory failure. Treatment with TAK-242 resulted in mild increases in serum methemoglobin levels but was otherwise well tolerated. Although observed mortality rates in patients with both shock and respiratory failure were lower with the 2.4 mg/kg/day dose, differences were not significant.

Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus.

BACKGROUND: Alternative therapies for Staphylococcus aureus bacteremia and endocarditis are needed. METHODS: We randomly assigned 124 patients with S. aureus bacteremia with or without endocarditis to receive 6 mg of daptomycin intravenously per kilogram of body weight daily and 122 to receive initial low-dose gentamicin plus either an antistaphylococcal penicillin or vancomycin. The primary efficacy end point was treatment success 42 days after the end of therapy. RESULTS: Forty-two days after the end of therapy in the modified intention-to-treat analysis, a successful outcome was documented for 53 of 120 patients who received daptomycin as compared with 48 of 115 patients who received standard therapy (44.2 percent vs. 41.7 percent; absolute difference, 2.4 percent; 95 percent confidence interval, -10.2 to 15.1 percent). Our results met prespecified criteria for the noninferiority of daptomycin. The success rates were similar in subgroups of patients with complicated bacteremia, right-sided endocarditis, and methicillin-resistant S. aureus. Daptomycin therapy was associated with a higher rate of microbiologic failure than was standard therapy (19 vs. 11 patients, P=0.17). In 6 of the 19 patients with microbiologic failure in the daptomycin group, isolates with reduced susceptibility to daptomycin emerged; similarly, a reduced susceptibility to vancomycin was noted in isolates from patients treated with vancomycin. As compared with daptomycin therapy, standard therapy was associated with a nonsignificantly higher rate of adverse events that led to treatment failure due to the discontinuation of therapy (17 vs. 8, P=0.06). Clinically significant renal dysfunction occurred in 11.0 percent of patients who received daptomycin and in 26.3 percent of patients who received standard therapy (P=0.004). CONCLUSIONS: Daptomycin (6 mg per kilogram daily) is not inferior to standard therapy for S. aureus bacteremia and right-sided endocarditis. (ClinicalTrials.gov number, NCT00093067 [ClinicalTrials.gov].).

Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial.

BACKGROUND: Invasive candidosis is increasingly prevalent in seriously ill patients. Our aim was to compare micafungin with liposomal amphotericin B for the treatment of adult patients with candidaemia or invasive candidosis. METHODS: We did a double-blind, randomised, multinational non-inferiority study to compare micafungin (100 mg/day) with liposomal amphotericin B (3 mg/kg per day) as first-line treatment of candidaemia and invasive candidosis. The primary endpoint was treatment success, defined as both a clinical and a mycological response at the end of treatment. Primary analyses were done on a per-protocol basis. This trial is registered with ClinicalTrials.gov, number NCT00106288. FINDINGS: 264 individuals were randomly assigned to treatment with micafungin; 267 were randomly assigned to receive liposomal amphotericin B. 202 individuals in the micafungin group and 190 in the liposomal amphotericin B group were included in the per-protocol analyses. Treatment success was observed for 181 (89.6%) patients treated with micafungin and 170 (89.5%) patients treated with liposomal amphotericin B. The difference in proportions, after stratification by neutropenic status at baseline, was 0.7% (95% CI -5.3 to 6.7). Efficacy was independent of the Candida spp and primary site of infection, as well as neutropenic status, APACHE II score, and whether a catheter was removed or replaced during the study. There were fewer treatment-related adverse events--including those that were serious or led to treatment discontinuation--with micafungin than there were with liposomal amphotericin B. INTERPRETATION: Micafungin was as effective as--and caused fewer adverse events than--liposomal amphotericin B as first-line treatment of candidaemia and invasive candidosis.

Preinduction glycemia and body mass index are important predictors of perioperative insulin management in patients undergoing cardiac surgery.

STUDY OBJECTIVE: To investigate whether preinduction glucose is an important predictor for perioperative insulin management in patients undergoing cardiac surgery. DESIGN: Prospective cohort study. SETTING: Large community hospital. PATIENTS: 80 consecutive patients scheduled for cardiac surgery. INTERVENTIONS: Patients were subdivided into those with a preinduction blood glucose of 110 mg/dL or lower with or without history of diabetes (group 1) and those with a preinduction blood glucose of above 110 mg/dL with or without history of diabetes (group 2). In group 1, there were no known diabetics. In group 2, 31% (11/35) had diabetes (group 2DM), while 24/35 (69%) did not (group 2NDM). An insulin infusion was started intraoperatively and adjusted according to a strict protocol in order to maintain normoglycemia (80-110 mg/dL) until discharge from intensive care. MEASUREMENTS AND MAIN RESULTS: In patients with preinduction glucose above 110 mg/dL, whether or not previously treated for diabetes, perioperative insulin requirements were higher, and intraoperative insulin management was more difficult than in those with lower preinduction glucose. In patients with a preinduction glucose above 110 mg/dL, hospital stay was longer, and inhospital mortality was significantly higher than in those with lower preinduction glucose. Multivariate analyses showed that preinduction glycemia was a good predictor of intraoperative insulin consumption, as was the body mass index (BMI) for intensive care and total insulin needs. CONCLUSIONS: In cardiac surgical patients with a preinduction glucose above 110 mg/dL, even if diabetes was not previously suspected, perioperative insulin requirements were higher, and intraoperative insulin management is more difficult than in those with a preinduction glucose 110 mg/dL or lower. Preinduction glycemia and BMI are good predictors of perioperative insulin management. Preinduction glycemia above 110 mg/dL predicts difficult perioperative glucose control and, moreover, that a preinduction blood glucose of 110 mg/dL or lower is associated with less insulin need.

Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial.

CONTEXT: The expression and release of tissue factor is a major trigger for the activation of coagulation in patients with sepsis. Tissue factor pathway inhibitor (TFPI) forms a complex with tissue factor and blood protease factors leading to inhibition of thrombin generation and fibrin formation. OBJECTIVES: To determine if administration of tifacogin (recombinant TFPI) provides mortality benefit in patients with severe sepsis and elevated international normalized ratio (INR) and to assess tifacogin safety in severe sepsis, including patients with low INR. DESIGN AND SETTING: A randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trial conducted from March 21, 2000, through September 27, 2001, in 245 hospitals in 17 countries in North America, Europe, and Israel. PATIENTS: The primary efficacy population consisted of 1754 patients (> or =18 years) with severe sepsis and a high INR (> or =1.2) randomly assigned to intravenous infusion of either tifacogin (0.025 mg/kg per hour for 96 hours, n = 880) or placebo (arginine citrate buffer, n = 874), and 201 patients with a low INR (<1.2) randomly assigned to receive the same dose of either tifacogin or placebo. MAIN OUTCOME MEASURE: All-cause 28-day mortality. RESULTS: Overall mortality at 28 days in the tifacogin-treated group (n = 880) vs the placebo group (n = 874) for high INR was 34.2% vs 33.9%, respectively (P =.88, Pearson chi2 test; P =.75, logistic regression model). None of the protocol-specified secondary end points differed between the tifacogin vs placebo groups. An analysis on the first 722 patients demonstrated a mortality rate of 38.9% for placebo vs 29.1% for tifacogin (P =.006, Pearson chi2 test). Tifacogin significantly attenuated prothrombin fragment 1.2 and thrombin:antithrombin complex levels (P<.001, 2-sample t test) in patients with high and low INR. Overall mortality was lower in the tifacogin response in patients with low INR (12%; n = 83) vs placebo (22.9%; n = 118) (P =.051, Pearson chi2 test; P =.03, logistic regression model). There was an increase in serious adverse events with bleeding in the tifacogin group in both cohorts (6.5% tifacogin and 4.8% placebo for high INR; 6.0% tifacogin and 3.3% placebo for low INR). CONCLUSIONS: Treatment with tifacogin had no effect on all-cause mortality in patients with severe sepsis and high INR. Tifacogin administration was associated with an increase in risk of bleeding, irrespective of baseline INR.

Effective reversal of moderate rocuronium- or vecuronium-induced neuromuscular block with sugammadex, a selective relaxant binding agent.

BACKGROUND: Sugammadex rapidly reverses rocuronium-induced neuromuscular block. This study explored the dose-response relation of sugammadex given as a reversal agent at reappearance of the second muscle twitch after rocuronium- and vecuronium-induced block. A secondary objective was to investigate the safety of single doses of sugammadex. METHODS: In this two-center, phase II, dose-finding study, 80 patients (age >or= 18 yr, American Society of Anesthesiologists physical status I or II, surgery >or= 60 min requiring muscle relaxation for intubation) were randomly assigned to receive rocuronium (0.60 mg/kg) or vecuronium (0.10 mg/kg). Sugammadex or placebo was administered at reappearance of the second muscle twitch. The primary efficacy endpoint was time from starting sugammadex administration until recovery of the train-of-four ratio to 0.9. RESULTS: Compared with placebo, sugammadex produced dose-dependent decreases in mean time to recovery for all train-of-four ratios in the rocuronium and vecuronium groups. The mean time for recovery of the train-of-four ratio to 0.9 in the rocuronium group was 31.8 min after placebo compared with 3.7 and 1.1 min after 0.5 and 4.0 mg/kg sugammadex, respectively. The mean time for recovery of the train-of-four ratio to 0.9 in the vecuronium group was 48.8 min after placebo, compared with 2.5 and 1.4 min after 1.0 and 8.0 mg/kg sugammadex, respectively. Sugammadex was well tolerated. CONCLUSION: Sugammadex rapidly reversed rocuronium- or vecuronium-induced neuromuscular block at reappearance of the second muscle twitch and was well tolerated. A dose-response relation was observed with sugammadex for reversal of both rocuronium- and vecuronium-induced neuromuscular block.

Effect of N2O on sevoflurane vaporizer settings during minimal- and low-flow anesthesia.

BACKGROUND: Uptake of a second gas of a delivered gas mixture decreases the amount of carrier gas and potent inhaled anesthetic leaving the circle system through the pop-off valve. The authors hypothesized that the vaporizer settings required to maintain constant end-expired sevoflurane concentration (Etsevo) during minimal-flow anesthesia (MFA, fresh gas flow of 0.5 l/min) or low-flow anesthesia (LFA, fresh gas flow of 1 l/min) would be lower when sevoflurane is used in oxygen-nitrous oxide than in oxygen. METHODS: Fifty-six patients receiving general anesthesia were randomly assigned to one of four groups (n = 14 each), depending on the carrier gas and fresh gas flow used: group Ox.5 l (oxygen, MFA), group NOx.5 l (oxygen-nitrous oxide, MFA after 10 min high fresh gas flow), group Ox1 l (oxygen, LFA), and group NOx1 l (oxygen-nitrous oxide, LFA after 10 min high fresh gas flow). The vaporizer dial settings required to maintain Etsevo at 1.3% were compared between groups. RESULTS: Vaporizer settings were higher in group Ox.5 l than in groups NOx.5 l, Ox1 l, and NOx1 l; vaporizer settings were higher in group NOx.5 l than in group NOx1 l between 23 and 47 min, and vaporizer settings did not differ between groups Ox1 l and NOx1 l. CONCLUSIONS: When using oxygen-nitrous oxide as the carrier gas, less gas and vapor are wasted through the pop-off valve than when 100% oxygen is used. During MFA with an oxygen-nitrous oxide mixture, when almost all of the delivered oxygen and nitrous oxide is taken up by the patient, the vaporizer dial setting required to maintain a constant Etsevo is lower than when 100% oxygen is used. With higher fresh gas flows (LFA), this effect of nitrous oxide becomes insignificant, presumably because the proportion of excess gas leaving the pop-off valve relative to the amount taken up by the patient increases. However, other unexplored factors affecting gas kinetics in a circle system may contribute to our observations.

Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial.

OBJECTIVE: Platelet-activating factor (PAF) and structurally-related oxidized phospholipids are proinflammatory mediators in systemic inflammatory states such as severe sepsis. The enzyme platelet-activating factor acetylhydrolase (PAF-AH) rapidly degrades PAF and oxidized phospholipids into inactive metabolites. Reduced PAF-AH activity has been observed in patients with severe sepsis and may contribute to their systemic inflammatory response and organ dysfunction. A previous clinical trial with recombinant human PAF-AH (rPAF-AH, Pafase) suggested that this treatment may decrease 28-day all-cause mortality in patients with severe sepsis. The current study was undertaken to confirm this result. DESIGN: A prospective, randomized, double-blind, placebo-controlled, multicenter, international trial. SETTING: One hundred forty-six intensive care units from nine countries. PATIENTS: Approximately 2,522 patients were planned to be enrolled < or =12 hrs after the onset of severe sepsis. Eligible patients were randomized to receive either rPAF-AH 1.0 mg/kg or placebo administered intravenously once daily for five consecutive days. MEASUREMENTS AND MAIN RESULTS: The study was terminated based on the recommendation of an independent data and safety monitoring committee after the second of three planned interim analyses, and the enrollment of 1,425 patients. rPAF-AH treatment was well tolerated among the 1,261 patients included in the interim analysis (643 rPAF-AH and 618 placebo), but did not decrease 28-day all-cause mortality compared with placebo (25% for rPAF-AH vs. 24% for placebo; relative risk, 1.03; 95% confidence interval, 0.85-1.25; p =.80). There were no statistically significant differences between treatment groups in any of the secondary efficacy end points. The overall incidence of adverse events was similar among rPAF-AH and placebo-treated patients, and no rPAF-AH-treated patients developed antibodies to PAF-AH. CONCLUSIONS: rPAF-AH was well tolerated and not antigenic, but did not decrease 28-day all-cause mortality in patients with severe sepsis.

The effect of anti-L-selectin (aselizumab) in multiple traumatized patients--results of a phase II clinical trial.

OBJECTIVE: The objectives of this study were to evaluate safety (primary) and clinical efficacy (secondary) of the humanized monoclonal anti-L-selectin antibody aselizumab in severely injured patients. DESIGN: Prospective phase II, parallel group, double-blind, randomized, placebo-controlled clinical trial. SETTING: Fourteen medical intensive care units or trauma units in level I trauma centers in Belgium, Germany, and Poland. PATIENTS: Eighty-four patients with a sustained trauma due to a blunt or penetrating injury and a total Injury Severity Scale score of > or =25. INTERVENTIONS: Patients received either aselizumab at dosages of 0.5, 1, or 2 mg/kg or placebo within 6 hrs of the traumatic event and were followed for 6 wks. MEASUREMENTS AND MAIN RESULTS: The number of expeditable adverse events increased dose dependently over the aselizumab groups compared with placebo. There were no statistically significant differences between all groups regarding leukopenia and risk of infection. No immunologic response following infusion of aselizumab was noted. The number of patients with multiple organ failure, defined as a median value of the total Goris Multiple Organ Failure score of > or =5 on > or =2 consecutive days within 14 days, was not significantly different for the 0.5 mg/kg, 1 mg/kg, 2 mg/kg, and placebo groups. There were no statistically significant differences in time of mechanical ventilation, length of stay in an intensive care unit, and total duration of hospitalization between treatment groups. CONCLUSIONS: Aselizumab was associated with a higher rate of infections and leucopenia; however, this difference was not significantly different compared with placebo. For all efficacy variables, aselizumab presented no significant trends but only a few scattered statistically significant differences between groups.