Interleukin-4 activates divergent cell-intrinsic signals to regulate retinal cell proliferation induced by classical growth factors.

In the developing retina, precise coordination of cell proliferation, differentiation, and survival is essential for proper retinal maturation and function. We have previously reported evidence that interleukin-4 (IL-4) plays critical roles in neuronal differentiation and survival during retinal development. However, little is known about the role of IL-4 on retinal cell proliferation. In the current study, we investigated if IL-4 regulates cell proliferation induced by epidermal growth factor (EGF) and by fibroblast growth factor 2 (FGF2) in primary retinal cell cultures obtained from newborn rats. First, we show that EGF and FGF2 act as mitogens for glial cells, increasing proliferation of these cells in the retina. EGF- and FGF2-induced mitogenesis requires activation of distinct cell-intrinsic signals. In retinal cells exposed to FGF2, IL-4 downregulates p53 levels (a protein whose activation induces cell-cycle arrest) and increases mitogenic responsiveness to FGF2 through activation of protein kinase A (PKA) pathway. Conversely, in retinal cells exposed to EGF, IL-4 downregulates cyclin D1 levels (a protein required for cell-cycle progression), upregulates p53 levels, and decreases mitogenic responsiveness to EGF. The inhibitory effect induced by IL-4 on retinal cells exposed to EGF requires activation of Janus kinase 3 (JAK3), but not activation of PKA. Based on previous and current findings, we propose that IL-4 serves as a node of signal divergence, modulating multiple cell-intrinsic signals (e.g., cyclin D1, p53, JAK3, and PKA) and mitogenic responsiveness to cell-extrinsic signals (e.g., FGF2 and EGF) to control cell proliferation, differentiation, and survival during retinal development.

Inducing Brain Cooling Without Core Temperature Reduction in Pigs Using a Novel Nasopharyngeal Method: An Effectiveness and Safety Study.

BACKGROUND: Acute brain lesions constitute an alarming public health concern. Neuroprotective therapies have been implemented to stabilize, prevent, or reduce brain lesions, thus improving neurological outcomes and survival rates. Hypothermia is the most effective approach, mainly attributed to the reduction in cellular metabolic activity. Whole-body cooling is currently implemented by healthcare professionals; however, adverse events are frequent, limiting the potential benefits of therapeutic hypothermia. Therefore, selective methods have been developed to reduce adverse events while delivering neuroprotection. Nasopharyngeal approaches are the safest and most effective methods currently considered. Our primary objective was to determine the effects of a novel nasopharyngeal catheter on the brain temperature of pigs. METHODS: In this prospective, non-randomized, interventional experimental trial, 10 crossbred pigs underwent nasopharyngeal cooling for 60 min followed by 15 min of rewarming. Nasopharyngeal catheters were inserted into the left nostril and properly positioned at the nasopharyngeal cavity. RESULTS: Nasopharyngeal cooling was associated with a decrease in brain temperature, which was more significant in the left cerebral hemisphere (p = 0.01). There was a reduction of 1.47 ± 0.86 °C in the first 5 min (p < 0.001), 2.45 ± 1.03 °C within 10 min (p < 0.001), and 4.45 ± 1.36 °C after 1 h (p < 0.001). The brain-core gradient was 4.57 ± 0.87 °C (p < 0.001). Rectal, esophageal, and pulmonary artery temperatures and brain and systemic hemodynamic parameters, remained stable during the procedure. Following brain cooling, values of oxygen partial pressure in brain tissue significantly decreased. No mucosal lesions were detected during nasal, pharyngeal, or oral inspection after nasopharyngeal catheter removal. CONCLUSIONS: In this study, a novel nasopharyngeal cooling catheter effectively induced and maintained exclusive brain cooling when combined with effective counter-warming methods. Exclusive brain cooling was safe with no device-related local or systemic complications and may be desired in selected patient populations.

Assessment of the peripheral microcirculation in patients with and without shock: a pilot study on different methods.

Microvascular dysfunction has been associated with adverse outcomes in critically ill patients, and the current concept of hemodynamic incoherence has gained attention. Our objective was to perform a comprehensive analysis of microcirculatory perfusion parameters and to investigate the best variables that could discriminate patients with and without circulatory shock during early intensive care unit (ICU) admission. This prospective observational study comprised a sample of 40 adult patients with and without circulatory shock (n = 20, each) admitted to the ICU within 24 h. Peripheral clinical [capillary refill time (CRT), peripheral perfusion index (PPI), skin-temperature gradient (Tskin-diff)] and laboratory [arterial lactate and base excess (BE)] perfusion parameters, in addition to near-infrared spectroscopy (NIRS)-derived variables were simultaneously assessed. While lactate, BE, CRT, PPI and Tskin-diff did not differ significantly between the groups, shock patients had lower baseline tissue oxygen saturation (StO2) [81 (76-83) % vs. 86 (76-90) %, p = 0.044], lower StO2min [50 (47-57) % vs. 55 (53-65)  %, p = 0.038] and lower StO2max [87 (80-92) % vs. 93 (90-95) %, p = 0.017] than patients without shock. Additionally, dynamic NIRS variables [recovery time (r = 0.56, p = 0.010), descending slope (r = - 0.44, p = 0.05) and ascending slope (r = - 0.54, p = 0.014)] and not static variable [baseline StO2 (r = - 0.24, p = 0.28)] exhibited a significant correlation with the administered dose of norepinephrine. In our study with critically ill patients assessed within the first twenty-four hours of ICU admission, among the perfusion parameters, only NIRS-derived parameters could discriminate patients with and without shock.

IGF-1 and IGF-1R modulate the effects of IL-4 on retinal ganglion cells survival: The involvement of M1 muscarinic receptor.

Trophic factors are involved in different cellular responses. Previously we demonstrated that IL-4 treatment induces an increase in retinal ganglion cell survival (RGCS) and regulates cholinergic differentiation of retinal cells in vitro. Data from literature show that IGF-1 also promotes RGCS, an effect mediated by PI-3K/AKT pathway. The aim of this study was to investigate the role of IGF-1 and IGF-1R on RGCS mediated by IL-4 treatment and the role of M1 acetylcholine receptors in this effect. Here we show that the effect of IL-4 on RGCS depends on IGF-1 and IGF-1R activation, the PI-3K/AKT and NFkB intracellular pathways and depends on M1 mAChRs activation. IGF-1 increases the levels of M1 mAChRs in 15min, 45min, 24 h and 48 h in mixed retinal cells culture, modulates the levels of IL-4, pIGF-1R, IGF-1R. IL-4 modulates IGF-1, pIGF-1R and IGF-1R levels in different time intervals. These results put in evidence a crosstalk between IL-4 and IGF-1 and a role of M1 mAChRs, IGF-1 and IGF-1R in RGCS mediated by IL-4.

Quality Improvement Initiatives in Sepsis in an Emerging Country: Does the Institution's Main Source of Income Influence the Results? An Analysis of 21,103 Patients.

OBJECTIVE: We aimed to assess the results of a quality improvement initiative in sepsis in an emerging setting and to analyze it according to the institutions' main source of income (public or private). DESIGN: Retrospective analysis of the Latin American Sepsis Institute database from 2005 to 2014. SETTINGS: Brazilian public and private institutions. PATIENTS: Patients with sepsis admitted in the participant institutions. INTERVENTIONS: The quality improvement initiative was based on a multifaceted intervention. The institutions were instructed to collect data on 6-hour bundle compliance and outcomes in patients with sepsis in all hospital settings. Outcomes and compliance was measured for eight periods of 6 months each, starting at the time of the enrollment in the intervention. The primary outcomes were hospital mortality and compliance with 6-hour bundle. MEASUREMENTS AND MAIN RESULTS: We included 21,103 patients; 9,032 from public institutions and 12,071 from private institutions. Comparing the first period with the eigth period, compliance with the 6-hour bundle increased from 13.5% to 58.2% in the private institutions (p < 0.0001) and from 7.4% to 15.7% in the public institutions (p < 0.0001). Mortality rates significantly decreased throughout the program in private institutions, from 47.6% to 27.2% in the eighth period (adjusted odds ratio, 0.45; 95% CI, 0.32-0.64). However, in the public hospitals, mortality diminished significantly only in the first two periods. CONCLUSION: This quality improvement initiative in sepsis in an emerging country was associated with a reduction in mortality and with improved compliance with quality indicators. However, this reduction was sustained only in private institutions.

Smart Care™ versus respiratory physiotherapy-driven manual weaning for critically ill adult patients: a randomized controlled trial.

INTRODUCTION: A recent meta-analysis showed that weaning with SmartCare™ (Dräger, Lübeck, Germany) significantly decreased weaning time in critically ill patients. However, its utility compared with respiratory physiotherapist-protocolized weaning is still a matter of debate. We hypothesized that weaning with SmartCare™ would be as effective as respiratory physiotherapy-driven weaning in critically ill patients. METHODS: Adult critically ill patients mechanically ventilated for more than 24 hours in the adult intensive care unit of the Albert Einstein Hospital, São Paulo, Brazil, were randomly assigned to be weaned either by progressive discontinuation of pressure support ventilation (PSV) with SmartCare™. Demographic data, respiratory function parameters, level of PSV, tidal volume (VT), positive end-expiratory pressure (PEEP), inspired oxygen fraction (FIO2), peripheral oxygen saturation (SpO2), end-tidal carbon dioxide concentration (EtCO2) and airway occlusion pressure at 0.1 second (P0.1) were recorded at the beginning of the weaning process and before extubation. Mechanical ventilation time, weaning duration and rate of extubation failure were compared. RESULTS: Seventy patients were enrolled 35 in each group. There was no difference between the two groups concerning age, sex or diagnosis at study entry. There was no difference in maximal inspiratory pressure, maximal expiratory pressure, forced vital capacity or rapid shallow breathing index at the beginning of the weaning trial. PEEP, VT, FIO2, SpO2, respiratory rate, EtCO2 and P0.1 were similar between the two groups, but PSV was not (median: 8 vs. 10 cmH2O; p =0.007). When the patients were ready for extubation, PSV (8 vs. 5 cmH2O; p =0.015) and PEEP (8 vs. 5 cmH2O; p <0.001) were significantly higher in the respiratory physiotherapy-driven weaning group. Total duration of mechanical ventilation (3.5 [2.0-7.3] days vs. 4.1 [2.7-7.1] days; p =0.467) and extubation failure (2 vs. 2; p =1.00) were similar between the two groups. Weaning duration was shorter in the respiratory physiotherapy-driven weaning group (60 [50-80] minutes vs. 110 [80-130] minutes; p <0.001). CONCLUSION: A respiratory physiotherapy-driven weaning protocol can decrease weaning time compared with an automatic system, as it takes into account individual weaning difficulties. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02122016 . Date of Registration: 27 August 2013.

Performance of noninvasive ventilation in acute respiratory failure in critically ill patients: a prospective, observational, cohort study.

BACKGROUND: Noninvasive ventilation (NIV) is used in critically ill patients with acute respiratory failure (ARF) to avoid endotracheal intubation. However, the impact of NIV use on ARF patient's outcomes is still unclear. Our objectives were to evaluate the rate of NIV failure in hypoxemic patients with an arterial carbon dioxide partial pressure (PaCO2) < 45 mmHg or ≥ 45 mmHg at ICU admission, the predictors of NIV failure, ICU and hospital length of stay and 28-day mortality. METHODS: Prospective single center cohort study. All consecutive patients admitted to a mixed ICU during a three-month period who received NIV, except for palliative care purposes, were included in this study. Demographic data, APACHE II score, cause of ARF, number of patients that received NIV, incidence of NIV failure, length of ICU, hospital stay and mortality rate were compared between NIV failure and success groups. RESULTS: Eighty-five from 462 patients (18.4 %) received NIV and 26/85 (30.6 %) required invasive mechanical ventilation. NIV failure patients were comparatively younger (67 ± 21 vs. 77 ± 14 years; p = 0.031), had lower arterial bicarbonate (p = 0.005), lower PaCO2 levels (p = 0.032), higher arterial lactate levels (p = 0.046) and APACHE II score (p = 0.034) compared to NIV success patients. NIV failure occurred in 25.0 % of patients with PaCO2 ≥ 45 mmHg and in 33.3 % of patients with PaCO2 < 45 mmHg (p = 0.435). NIV failure was associated with an increased risk of in-hospital death (OR 4.64, 95 % CI 1.52 to 14.18; p = 0.007) and length [median (IQR)] of ICU [12 days (8-31) vs. 2 days (1-4); p < 0.001] and hospital [30 (19-42) vs. 15 (9-33) days; p = 0.010] stay. Predictors of NIV failure included age (OR 0.96, 95 % CI 0.93 to 0.99; p = 0.007) and APACHE II score (OR 1.13, 95 % CI 1.02 to 1.25; p = 0.018). CONCLUSION: NIV failure was associated with an increased risk of in-hospital death, ICU and hospital stay and was not affected by baseline PaCO2 levels. Patients that failed were comparatively younger and had higher APACHE II score, suggesting the need for a careful selection of patients that might benefit from NIV. A well-designed study on the impact of a short monitored NIV trial on outcomes is needed.

Increasing mean arterial blood pressure in sepsis: effects on fluid balance, vasopressor load and renal function.

INTRODUCTION: The objective of this study was to evaluate the effects of two different mean arterial blood pressure (MAP) targets on needs for resuscitation, organ dysfunction, mitochondrial respiration and inflammatory response in a long-term model of fecal peritonitis. METHODS: Twenty-four anesthetized and mechanically ventilated pigs were randomly assigned (n = 8/group) to a septic control group (septic-CG) without resuscitation until death or one of two groups with resuscitation performed after 12 hours of untreated sepsis for 48 hours, targeting MAP 50-60 mmHg (low-MAP) or 75-85 mmHg (high-MAP). RESULTS: MAP at the end of resuscitation was 56 ± 13 mmHg (mean ± SD) and 76 ± 17 mmHg respectively, for low-MAP and high-MAP groups. One animal each in high- and low-MAP groups, and all animals in septic-CG died (median survival time: 21.8 hours, inter-quartile range: 16.3-27.5 hours). Norepinephrine was administered to all animals of the high-MAP group (0.38 (0.21-0.56) mcg/kg/min), and to three animals of the low-MAP group (0.00 (0.00-0.25) mcg/kg/min; P = 0.009). The high-MAP group had a more positive fluid balance (3.3 ± 1.0 mL/kg/h vs. 2.3 ± 0.7 mL/kg/h; P = 0.001). Inflammatory markers, skeletal muscle ATP content and hemodynamics other than MAP did not differ between low- and high-MAP groups. The incidence of acute kidney injury (AKI) after 12 hours of untreated sepsis was, respectively for low- and high-MAP groups, 50% (4/8) and 38% (3/8), and in the end of the study 57% (4/7) and 0% (P = 0.026). In septic-CG, maximal isolated skeletal muscle mitochondrial Complex I, State 3 respiration increased from 1357 ± 149 pmol/s/mg to 1822 ± 385 pmol/s/mg, (P = 0.020). In high- and low-MAP groups, permeabilized skeletal muscle fibers Complex IV-state 3 respiration increased during resuscitation (P = 0.003). CONCLUSIONS: The MAP targets during resuscitation did not alter the inflammatory response, nor affected skeletal muscle ATP content and mitochondrial respiration. While targeting a lower MAP was associated with increased incidence of AKI, targeting a higher MAP resulted in increased net positive fluid balance and vasopressor load during resuscitation. The long-term effects of different MAP targets need to be evaluated in further studies.

Insulin-like growth factor-1 stimulates retinal cell proliferation via activation of multiple signaling pathways.

Insulin-like growth factor-1 (IGF-1) plays critical roles in the development of the central nervous system (CNS), including the retina, regulating cell proliferation, differentiation, and survival. Here, we investigated the role of IGF-1 on retinal cell proliferation using primary cultures from rat neural retina. Our data show that IGF-1 stimulates retinal cell proliferation and regulates the expression of neurotrophic factors, such as interleukin-4 and brain-derived neurotrophic factor. In addition, our results indicates that IGF-1-induced retinal cell proliferation requires activation of multiple signaling pathways, including phosphatidylinositol 3-kinase, protein kinase Src, phospholipase-C, protein kinase C delta, and mitogen-activated protein kinase pathways. We further show that activation of matrix metalloproteinases and epidermal growth factor receptor is also necessary for IGF-1 enhancing retinal cell proliferation. Overall, these results unveil potential mechanisms by which IGF-1 ensures retinal cell proliferation and support the notion that manipulation of IGF-1 signaling may be beneficial in CNS disorders associated with abnormal cell proliferation.

Effect of treatment delay on disease severity and need for resuscitation in porcine fecal peritonitis.

OBJECTIVE: Early treatment in sepsis may improve outcome. The aim of this study was to evaluate how the delay in starting resuscitation influences the severity of sepsis and the treatment needed to achieve hemodynamic stability. DESIGN: Prospective, randomized, controlled experimental study. SETTING: Experimental laboratory in a university hospital. SUBJECTS: Thirty-two anesthetized and mechanically ventilated pigs. INTERVENTIONS: Pigs were randomly assigned (n=8 per group) to a nonseptic control group or one of three groups in which fecal peritonitis (peritoneal instillation of 2 g/kg autologous feces) was induced, and a 48-hr period of protocolized resuscitation started 6 (ΔT-6 hrs), 12 (ΔT-12 hrs), or 24 (ΔT-24 hrs) hrs later. The aim of this study was to evaluate the impact of delays in resuscitation on disease severity, need for resuscitation, and the development of sepsis-associated organ and mitochondrial dysfunction. MEASUREMENTS AND MAIN RESULTS: Any delay in starting resuscitation was associated with progressive signs of hypovolemia and increased plasma levels of interleukin-6 and tumor necrosis factor-α prior to resuscitation. Delaying resuscitation increased cumulative net fluid balances (2.1±0.5 mL/kg/hr, 2.8±0.7 mL/kg/hr, and 3.2±1.5 mL/kg/hr, respectively, for groups ΔT-6 hrs, ΔT-12 hrs, and ΔT-24 hrs; p<.01) and norepinephrine requirements during the 48-hr resuscitation protocol (0.02±0.04 µg/kg/min, 0.06±0.09 µg/kg/min, and 0.13±0.15 µg/kg/min; p=.059), decreased maximal brain mitochondrial complex II respiration (p=.048), and tended to increase mortality (p=.08). Muscle tissue adenosine triphosphate decreased in all groups (p<.01), with lowest values at the end in groups ΔT-12 hrs and ΔT-24 hrs. CONCLUSIONS: Increasing the delay between sepsis initiation and resuscitation increases disease severity, need for resuscitation, and sepsis-associated brain mitochondrial dysfunction. Our results support the concept of a critical window of opportunity in sepsis resuscitation.

The effects of low and high tidal volume and pentoxifylline on intestinal blood flow and leukocyte-endothelial interactions in mechanically ventilated rats.

BACKGROUND: The combination of high PEEP and low tidal volume (V(T)) decreases some risks of mechanical ventilation, including pulmonary overdistention, damage due to cyclic opening and closing of the alveoli, and inflammatory responses that can lead to multiple-organ dysfunction. We hypothesized that high V(T) and high PEEP induce mesenteric microcirculatory disturbances and that those disturbances would be attenuated by pentoxifylline, which is anti-inflammatory. METHODS: We anesthetized (isoflurane 1.5%), tracheostomized, and mechanically ventilated 57 male Wistar rats with PEEP of 10 cm H(2)O and F(IO(2)) of 0.21 for 2 hours. One group received low V(T) (7 mL/kg), another group received high V(T) (10 mL/kg), and a third group received high V(T) plus pentoxifylline (25 mg/kg). We measured mean arterial pressure, respiratory mechanics, mesenteric blood flow, and leukocyte-endothelial interactions. RESULTS: The mean arterial pressure was similar among the groups at baseline (108 mm Hg [IQR 94-118 mm Hg]) and after 2 hours of mechanical ventilation (104 mm Hg [IQR 90-114 mm Hg]). Mesenteric blood flow was also similar between the groups: low V(T) 15.1 mL/min (IQR 12.4-17.7 mL/min), high V(T) 11.3 mL/min (IQR 8.6-13.8 mL/min), high-V(T)/pentoxifylline 12.4 mL/min (10.8-13.7 mL/min). Peak airway pressure after 2 hours was lower (P = .03) in the low-V(T) group (10.4 cm H(2)O [IQR 10.2-10.4 cm H(2)O]) than in the high-V(T) group (12.6 cm H(2)O [10.2-14.9 cm H(2)O]) or the high-V(T)/pentoxifylline group (12.8 cm H(2)O [10.7-16.0 cm H(2)O]). There were fewer adherent leukocytes (P = .005) and fewer migrated leukocytes (P = .002) in the low-V(T) group (5 cells/100 µm length [IQR 4-7 cells/100 µm length] and 1 cell/5,000 µm(2) [IQR 1-2 cells/5,000 µm(2)], respectively) and the high-V(T)/pentoxifylline group (5 cells/100 µm length [IQR 3-10 cells/100 µm length] and 1 cell/5,000 µm(2) [IQR 1-3 cells/5,000 µm(2)], respectively) than in the high-V(T) group (14 cells/100 µm length [IQR 11-16 cells/100 µm length] and 9 cells/5,000 µm(2) [IQR 8-12 cells/5,000 µm(2)], respectively). CONCLUSIONS: Low V(T) with high PEEP was lung-protective, and early pentoxifylline reduced the inflammatory response to high V(T) with high PEEP (and presumed lung overdistention) during mechanical ventilation.

The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis.

OBJECTIVE: The Surviving Sepsis Campaign (SSC or "the Campaign") developed guidelines for management of severe sepsis and septic shock. A performance improvement initiative targeted changing clinical behavior (process improvement) via bundles based on key SSC guideline recommendations. DESIGN AND SETTING: A multifaceted intervention to facilitate compliance with selected guideline recommendations in the intensive care unit, emergency department, and wards of individual hospitals and regional hospital networks was implemented voluntarily in the United States, Europe, and South America. Elements of the guidelines were "bundled" into two sets of targets to be completed within 6 hrs and within 24 hrs. An analysis was conducted on data submitted from January 2005 through March 2008. SUBJECTS: A total of 15,022 subjects. MEASUREMENTS AND MAIN RESULTS: Data from 15,022 subjects at 165 sites were analyzed to determine the compliance with bundle targets and association with hospital mortality. Compliance with the entire resuscitation bundle increased linearly from 10.9% in the first site quarter to 31.3% by the end of 2 yrs (p < .0001). Compliance with the entire management bundle started at 18.4% in the first quarter and increased to 36.1% by the end of 2 yrs (p = .008). Compliance with all bundle elements increased significantly, except for inspiratory plateau pressure, which was high at baseline. Unadjusted hospital mortality decreased from 37% to 30.8% over 2 yrs (p = .001). The adjusted odds ratio for mortality improved the longer a site was in the Campaign, resulting in an adjusted absolute drop of 0.8% per quarter and 5.4% over 2 yrs (95% confidence interval, 2.5-8.4). CONCLUSIONS: The Campaign was associated with sustained, continuous quality improvement in sepsis care. Although not necessarily cause and effect, a reduction in reported hospital mortality rates was associated with participation. The implications of this study may serve as an impetus for similar improvement efforts.

Characteristics and outcomes of patients with cancer requiring admission to intensive care units: a prospective multicenter study.

OBJECTIVE: To evaluate the characteristics and outcomes of patients with cancer admitted to several intensive care units. Knowledge on patients with cancer requiring intensive care is mostly restricted to single-center studies. DESIGN: : Prospective, multicenter, cohort study. SETTING: Intensive care units from 28 hospitals in Brazil. PATIENTS: A total of 717 consecutive patients included over a 2-mo period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 667 (93%) patients with solid tumors and 50 (7%) patients had hematologic malignancies. The main reasons for intensive care unit admission were postoperative care (57%), sepsis (15%), and respiratory failure (10%). Overall hospital mortality rate was 30% and was higher in patients admitted because of medical complications (58%) than in emergency (37%) and scheduled (11%) surgical patients (p < .001). Adjusting for covariates other than the type of admission, the number of hospital days before intensive care unit admission (odds ratio [OR], 1.18; 95% confidence interval [CI], 1.01-1.37), higher Sequential Organ Failure Assessment scores (OR, 1.25; 95% CI, 1.17-1.34), poor performance status (OR, 3.40; 95% CI, 2.19 -5.26), the need for mechanical ventilation (OR, 2.42; 95% CI, 1.51-3.87), and active underlying malignancy in recurrence or progression (OR, 2.42; 95% CI, 1.51-3.87) were associated with increased hospital mortality in multivariate analysis. CONCLUSIONS: This large multicenter study reports encouraging survival rates for patients with cancer requiring intensive care. In these patients, mortality was mostly dependent on the severity of organ failures, performance status, and need for mechanical ventilation rather than cancer-related characteristics, such as the type of malignancy or the presence of neutropenia.

Global utilization of low-dose corticosteroids in severe sepsis and septic shock: a report from the PROGRESS registry.

INTRODUCTION: The benefits and use of low-dose corticosteroids (LDCs) in severe sepsis and septic shock remain controversial. Surviving sepsis campaign guidelines suggest LDC use for septic shock patients poorly responsive to fluid resuscitation and vasopressor therapy. Their use is suspected to be wide-spread, but paucity of data regarding global practice exists. The purpose of this study was to compare baseline characteristics and clinical outcomes of patients treated or not treated with LDC from the international PROGRESS (PROmoting Global Research Excellence in Severe Sepsis) cohort study of severe sepsis. METHODS: Patients enrolled in the PROGRESS registry were evaluated for use of vasopressor and LDC (equivalent or lesser potency to hydrocortisone 50 mg six-hourly plus 50 microg 9-alpha-fludrocortisone) for treatment of severe sepsis at any time in intensive care units (ICUs). Baseline characteristics and hospital mortality were analyzed, and logistic regression techniques used to develop propensity score and outcome models adjusted for baseline imbalances between groups. RESULTS: A total of 8,968 patients with severe sepsis and sufficient data for analysis were studied. A total of 79.8% (7,160/8,968) of patients received vasopressors, and 34.0% (3,051/8,968) of patients received LDC. Regional use of LDC was highest in Europe (51.1%) and lowest in Asia (21.6%). Country use was highest in Brazil (62.9%) and lowest in Malaysia (9.0%). A total of 14.2% of patients on LDC were not receiving any vasopressor therapy. LDC patients were older, had more co-morbidities and higher disease severity scores. Patients receiving LDC spent longer in ICU than patients who did not (median of 12 versus 8 days; P <0.001). Overall hospital mortality rates were greater in the LDC than in the non-LDC group (58.0% versus 43.0%; P <0.001). After adjusting for baseline imbalances, in all mortality models (with vasopressor use), a consistent association remained between LDC and hospital mortality (odds ratios varying from 1.30 to 1.47). CONCLUSIONS: Widespread use of LDC for the treatment of severe sepsis with significant regional and country variation exists. In this study, 14.2% of patients received LDC despite the absence of evidence of shock. Hospital mortality was higher in the LDC group and remained higher after adjustment for key determinates of mortality.

Teicoplanin versus vancomycin for proven or suspected infection.

BACKGROUND: Vancomycin and teicoplanin are commonly used to treat gram-positive infections, particularly those caused by methicillin-resistant Staphylococcus aureus (MRSA). There is uncertainty regarding the effects of teicoplanin compared to vancomycin on kidney function with some previous studies suggesting teicoplanin is less nephrotoxic than vancomycin. OBJECTIVES: To investigate the efficacy and safety of vancomycin versus teicoplanin in patients with proven or suspected infection. SEARCH STRATEGY: We searched the Cochrane Renal Group's Specialised Register, CENTRAL, MEDLINE, EMBASE, reference lists of nephrology textbooks, review articles with relevant studies and sent letters seeking information about unpublished or incomplete studies to investigators involved in previous studies. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) in any language comparing teicoplanin to vancomycin for patients with proven or suspected infection. DATA COLLECTION AND ANALYSIS: Two authors independently evaluated methodological quality and extracted data using standardised data extraction forms. Study investigators were contacted for information not available in the original manuscripts. Random effects model was used to estimate the pooled risk ratio (RR) with 95% confidence interval (CI). MAIN RESULTS: We included 24 studies (2,610 patients) in this review. Teicoplanin reduced the risk of nephrotoxicity compared to vancomycin (RR 0.66, 95% CI 0.48 to 0.90).The effects of teicoplanin or vancomycin were similar for clinical cure (RR 1.03, 95% CI 0.98 to 1.08), microbiological cure (RR 0.98, 95% CI 0.93 to 1.03) and mortality (RR 1.02, 95% CI 0.79 to1.30). Six studies reported no cases of acute kidney injury (AKI) needing dialysis. Adverse events were less frequent with teicoplanin including cutaneous rash (RR 0.57, 95% CI 0.35 to 0.92), red man syndrome (RR 0.21, 95% CI 0.08 to 0.59) and total adverse events (RR 0.73, 95% CI 0.53 to 1.00). A lower risk of nephrotoxicity with teicoplanin was observed in patients either with (RR 0.51, 95% CI 0.30 to 0.88) or without aminoglycosides (RR 0.31, 95% 0.07 to 1.50), and also when vancomycin dosing was guided by serum levels (RR 0.22, 95% CI 0.10 to 0.52). AUTHORS' CONCLUSIONS: Teicoplanin and vancomycin are both effective in treating those with proven or suspected infection; however the incidence of adverse effects including nephrotoxicity was lower with teicoplanin. There were no cases of AKI needing dialysis. It remains unclear whether the differential effect on kidney function should influence which antibiotic be prescribed, although it may be reasonable to consider teicoplanin for patients at higher risk for AKI needing dialysis.

Quality improvement model (IHI) as a strategy to implement a sepsis protocol in a public hospital in Brazil.

A major challenge for hospitals in low-income and middle-income countries is to improve management of patients diagnosed with sepsis. The objective of the present study was to evaluate the Institute for Healthcare Improvement (IHI) Model as a strategy to implement a managed sepsis protocol aimed at reducing sepsis mortality. We performed a longitudinal, prospective, non-randomised study using PDSA cycles for translating and implementing improvement actions and tools. Baseline case mortality/case fatality data were collected, and compliance rates were evaluated according to the Surviving Sepsis Campaign guidelines (3-hour care-bundle). Sepsis multidisciplinary work teams were designated and were responsible to develop Driver Diagrams and implement process changes in the intensive care unit, wards and emergency department. Satisfaction levels of healthcare professionals were assessed (balance variables). The study was carried out in a public quaternary hospital, in São Paulo city, Brazil (Hospital Municipal da Vila Santa Catarina). The number of patients with sepsis studied was 416 who were followed over a 15-month period. The data analyses were carried out by statistical process control. Case fatality rates were kept below a prespecified target of 25% (15.9%) during the period. Satisfaction level of the participating staff was high (95.2%) and 71% of participants reported no work overload. The IHI model was found to be a feasible and useful strategy for implementing a sepsis management clinical protocol.

Comparison of three transfusion protocols prior to central venous catheterization in patients with cirrhosis: A randomized controlled trial.

BACKGROUND: Transfusion of blood components prior to invasive procedures in cirrhosis patients is high and associated with adverse events. OBJECTIVES: We compared three transfusion strategies prior to central venous catheterization in cirrhosis patients. PATIENTS/METHODS: Single center randomized trial that included critically ill cirrhosis patients with indication for central venous line in a tertiary private hospital in Brazil. INTERVENTIONS: Restrictive protocol, thromboelastometry-guided protocol, or usual care (based on coagulogram). The primary endpoint was the proportion of patients transfused with any blood component (ie, fresh frozen plasma, platelets, or cryoprecipitate). The secondary endpoints included incidence of bleeding and transfusion-related adverse events. RESULTS: A total of 57 patients (19 per group; 64.9% male; mean age, 53.4 ± 11.3 years) were enrolled. Prior to catheterization, 3/19 (15.8%) in the restrictive arm, 13/19 (68.4%) in the thromboelastometry-guided arm, and 14/19 (73.7%) in the coagulogram-guided arm received blood transfusion (odds ratio [OR], 0.07; 95% confidence interval [CI], 0.01-0.45; P = .002 for restrictive versus coagulogram-guided arm; OR, 0.09; 95% CI, 0.01-0.56; P = .006 for restrictive versus thromboelastometry-guided arm; and OR, 0.77; 95% CI, 0.14-4.15; P = .931 for thromboelastometry-guided versus coagulogram-guided arm). The restrictive protocol was cost saving. No difference in bleeding, length of stay, mortality, and transfusion-related adverse events was found. CONCLUSIONS: The use of a restrictive strategy is associated with a reduction in transfusion prior to central venous catheterization and costs in critically ill cirrhosis patients. No effect on bleeding was found among the groups.

Effects of hydrocortisone on microcirculatory alterations in patients with septic shock.

OBJECTIVE: To evaluate the effects of hydrocortisone on microcirculatory blood flow alterations in patients with septic shock. DESIGN: Prospective, open-label study. SETTING: A 31-bed, medico-surgical intensive care unit of a university hospital. PATIENTS: Twenty patients with septic shock. INTERVENTIONS: Intravenous hydrocortisone (50 mg/6 hr). MEASUREMENTS AND MAIN RESULTS: An orthogonal polarization spectral device (Cytoscan ARII, Cytometrics; Philadelphia, PA) was used to investigate the sublingual microcirculation in 20 patients who received so-called "stress doses" of hydrocortisone as part of their management for septic shock. Hemodynamic measurements and orthogonal polarization spectral images were obtained before administration of the first dose (50 mg) of hydrocortisone and 1, 2, 4, and 24 hours later. Measurements were also made before an adrenocorticotropic hormone (ACTH) test, whenever performed. Global hemodynamic variables were similar at all study time points. Microcirculatory variables improved slightly already at 1 hour after the start of hydrocortisone administration. In particular, perfused vessel density increased from 5.7 (4.8-6.4) to 7.2 (6.5-9.0)n/mm, p < 0.01, which was due to combined increases in small vessel density from 5.2 (4.6-6.2) to 6.0 (5.1-7.5)n/mm, p < 0.01, and in the proportion of perfused vessels from 82.1 (68.7-88.0) to 89.2 (83.4-92.6)%, p < 0.01. There were no differences in microcirculatory variables during hydrocortisone administration between ACTH test responders and nonresponders. CONCLUSIONS: The administration of moderate doses of hydrocortisone in septic shock results in a modest but consistent improvement in capillary perfusion, independent of the response to the ACTH test. The mechanisms underlying this effect need to be elucidated.

Automatic versus manual pressure support reduction in the weaning of post-operative patients: a randomised controlled trial.

INTRODUCTION: Reduction of automatic pressure support based on a target respiratory frequency or mandatory rate ventilation (MRV) is available in the Taema-Horus ventilator for the weaning process in the intensive care unit (ICU) setting. We hypothesised that MRV is as effective as manual weaning in post-operative ICU patients. METHODS: There were 106 patients selected in the post-operative period in a prospective, randomised, controlled protocol. When the patients arrived at the ICU after surgery, they were randomly assigned to either: traditional weaning, consisting of the manual reduction of pressure support every 30 minutes, keeping the respiratory rate/tidal volume (RR/TV) below 80 L until 5 to 7 cmH2O of pressure support ventilation (PSV); or automatic weaning, referring to MRV set with a respiratory frequency target of 15 breaths per minute (the ventilator automatically decreased the PSV level by 1 cmH2O every four respiratory cycles, if the patient's RR was less than 15 per minute). The primary endpoint of the study was the duration of the weaning process. Secondary endpoints were levels of pressure support, RR, TV (mL), RR/TV, positive end expiratory pressure levels, FiO2 and SpO2 required during the weaning process, the need for reintubation and the need for non-invasive ventilation in the 48 hours after extubation. RESULTS: In the intention to treat analysis there were no statistically significant differences between the 53 patients selected for each group regarding gender (p = 0.541), age (p = 0.585) and type of surgery (p = 0.172). Nineteen patients presented complications during the trial (4 in the PSV manual group and 15 in the MRV automatic group, p < 0.05). Nine patients in the automatic group did not adapt to the MRV mode. The mean +/- sd (standard deviation) duration of the weaning process was 221 +/- 192 for the manual group, and 271 +/- 369 minutes for the automatic group (p = 0.375). PSV levels were significantly higher in MRV compared with that of the PSV manual reduction (p < 0.05). Reintubation was not required in either group. Non-invasive ventilation was necessary for two patients, in the manual group after cardiac surgery (p = 0.51). CONCLUSIONS: The duration of the automatic reduction of pressure support was similar to the manual one in the post-operative period in the ICU, but presented more complications, especially no adaptation to the MRV algorithm. TRIAL REGISTRATION NUMBER: ISRCTN37456640.