Background: The aim of the present study was to investigate the incidence of adverse events (AEs) during intra-hospital transport (IHT) of critically ill patients and evaluate the risk factors associated with these events. Methods: This prospective multicenter observational study was performed in 34 intensive care units in China during 20 consecutive days from 5 November to 25 November 2012. All consecutive patients who required IHT for diagnostic testing or therapeutic procedures during the study period were included. All AEs that occurred during IHT were recorded. The incidence of AEs was defined as the rate of transports with at least one AE. The statistical analysis included a description of demographic and clinical characteristics of the cohort as well as identification of risk factors for AEs during IHT by univariate and multivariate logistic regression analyses. Results: In total, 441 IHTs of 369 critically ill patients were analyzed. The overall incidence of AEs was 79.8 % (352 IHTs). The proportion of equipment- and staff-related adverse events was 7.9 % (35 IHTs). The rate of patient-related adverse events (P-AEs) was 79.4 % (349 IHTs). The rates of vital sign–related P-AEs and arterial blood gas analysis–related P-AEs were 57.1 % (252 IHTs) and 46.9 % (207 IHTs), respectively. The incidence of critical P-AEs was 33.1 % (146 IHTs). The rates of vital sign–related critical P-AEs and arterial blood gas analysis–related critical P-AEs were 22.9 % (101 IHTs) and 15.0 % (66 IHTs), respectively. All data collected in our study were considered potential risk factors. In the multivariate analysis, predictive factors for P-AEs were pH, partial pressure of carbon dioxide in arterial blood, lactate level, glucose level, and heart rate before IHT. Furthermore, the Acute Physiology and Chronic Health Evaluation II score, partial pressure of oxygen in arterial blood, lactate level, glucose level, heart rate, respiratory rate, pulse oximetry, and sedation before transport were independent influential factors for critical P-AEs during IHT. Conclusions: The incidence of P-AEs during IHT of critically ill patients was high. Risk factors for P-AEs during IHT were identified. Strategies are needed to reduce their frequency.Trial registrationChinese Clinical Trial Register identifier ChiCTR-OCS-12002661. Registered 5 November 2012.

No description available

Background: High serum lactate is associated with increased mortality in septic shock patients. Metformin alters lactate metabolism, and may affect its prognostic value. We compared, between metformin users and nonusers, the prognosis of extremely elevated plasma lactate levels in patients with septic shock. Methods: The electronic medical records (EMR) of patients admitted to the emergency room between January 2011 and June 2013 were reviewed. The study cohort comprised patients with an initial diagnosis of septic shock and blood lactate higher than 10 mmol/L. The selected population was divided into two groups: metformin users (exposed) and metformin nonusers (unexposed). The primary outcome measured was inhospital mortality. Results: The study included 44 metformin users and 118 nonusers. Metformin users were similar to nonusers with respect to levels of lactate, HCO 3 , and blood pH; however, they were older and had higher incidence rates of cardiovascular disease and acute kidney injury at admission, compared to nonusers. Inhospital mortality rates were significantly lower in the metformin-treated group, 56.8 % vs. 88.1 %, p <0.0001. Conclusions: Though high lactate concentration indicates poor prognosis in septic patients, mortality rate was found to be significantly lower in those who were treated with metformin. This finding may help clinicians in deciding treatment for these patients, who could otherwise be considered too ill for real treatment benefit.

Background: Leukocyte-mediated pulmonary inflammation is a key pathophysiological mechanism involved in acute respiratory distress syndrome (ARDS). Massive sequestration of leukocytes in the pulmonary microvasculature is a major triggering event of the syndrome. We therefore investigated the potential role of leukocyte stiffness and adhesiveness in the sequestration of leukocytes in microvessels.  Methods: This study was based on in vitro microfluidic assays using patient sera. Cell stiffness was assessed by measuring the entry time (ET) of a single cell into a microchannel with a 6 × 9–?m cross-section under a constant pressure drop (?P = 160 Pa). Primary neutrophils and monocytes, as well as the monocytic THP-1 cell line, were used. Cellular adhesiveness to human umbilical vein endothelial cells was examined using the laminar flow chamber method. We compared the properties of cells incubated with the sera of healthy volunteers (n = 5), patients presenting with acute cardiogenic pulmonary edema (ACPE; n = 6), and patients with ARDS (n = 22), of whom 13 were classified as having moderate to severe disease and the remaining 9 as having mild disease.  Results: Rapid and strong stiffening of primary neutrophils and monocytes was induced within 30 minutes (mean ET >50 seconds) by sera from the ARDS group compared with both the healthy subjects and the ACPE groups (mean ET <1 second) (p < 0.05). Systematic measurements with the THP-1 cell line allowed for the establishment of a strong correlation between stiffening and the severity of respiratory status (mean ET 0.82 ± 0.08 seconds for healthy subjects, 1.6 ± 1.0 seconds for ACPE groups, 10.5 ± 6.1 seconds for mild ARDS, and 20.0 ± 8.1 seconds for moderate to severe ARDS; p < 0.05). Stiffening correlated with the cytokines interleukin IL-1?, IL-8, tumor necrosis factor TNF-?, and IL-10 but not with interferon-?, transforming growth factor-?, IL-6, or IL-17. Strong stiffening was induced by IL-1?, IL-8, and TNF-? but not by IL-10, and incubations with sera and blocking antibodies against IL-1?, IL-8, or TNF-? significantly diminished the stiffening effect of serum. In contrast, the measurements of integrin expression (CD11b, CD11a, CD18, CD49d) and leukocyte–endothelium adhesion showed a weak and slow response after incubation with the sera of patients with ARDS (several hours), suggesting a lesser role of leukocyte adhesiveness compared with leukocyte stiffness in early ARDS.  Conclusions: The leukocyte stiffening induced by cytokines in the sera of patients might play a role in the sequestration of leukocytes in the lung capillary beds during early ARDS. The inhibition of leukocyte stiffening with blocking antibodies might inspire future therapeutic strategies.

Background: Evidence suggests that EMS-physician-guided cardiopulmonary resuscitation (CPR) in out-of-hospital cardiac arrest (OOHCA) may be associated with improved outcomes, yet randomized controlled trials are not available. The goal of this meta-analysis was to determine the association between EMS-physician- versus paramedic-guided CPR and survival after OOHCA.Methods and ResultsStudies that compared EMS-physician- versus paramedic-guided CPR in OOHCA published until June 2014 were systematically searched in MEDLINE, EMBASE and Cochrane databases. All studies were required to contain survival data. Data on study characteristics, methods, and as well as survival outcomes were extracted. A random-effects model was used for the meta-analysis due to a high degree of heterogeneity among the studies (I 2 ?=?44 %). Return of spontaneous circulation [ROSC], survival to hospital admission, and survival to hospital discharge were the outcome measures.Out of 3,385 potentially eligible studies, 14 met the inclusion criteria. In the pooled analysis (n?=?126,829), EMS-physician-guided CPR was associated with significantly improved outcomes compared to paramedic-guided CPR: ROSC 36.2 % (95 % confidence interval [CI] 31.0 – 41.7 %) vs. 23.4 % (95 % CI 18.5 – 29.2 %) (pooled odds ratio [OR] 1.89, 95 % CI 1.36 – 2.63, p?<?0.001); survival to hospital admission 30.1 % (95 % CI 24.2 – 36.7 %) vs. 19.2 % (95 % CI 12.7 – 28.1 %) (pooled OR 1.78, 95 % CI 0.97 – 3.28, p?=?0.06); and survival to discharge 15.1 % (95 % CI 14.6 – 15.7 %) vs. 8.4 % (95 % CI 8.2 – 8.5 %) (pooled OR 2.03, 95 % CI 1.48 – 2.79, p?<?0.001). Conclusions: This systematic review suggests that EMS-physician-guided CPR in out-of-hospital cardiac arrest is associated with improved survival outcomes.

Glutamine is one of the conditionally essential free amino acids with multiple biological functions. Its supplementation to parenteral nutrition has been widely used for the management of complications in intensive care. However, controversial clinical reports have generated reluctance in the use of this pharmaco-nutrient. In this commentary, we address the impact of four studies that influenced the recommendations on glutamine supplementation by the Canadian Clinical Practice Guide 2015. Because of the importance of this guideline in clinical practice, we strongly believe that a more rigorous and critical evaluation is required to support recommendations in future guidelines.

Background: Electrical impedance tomography (EIT) is a non-invasive bedside tool which allows an individualized ventilator strategy by monitoring tidal ventilation and lung aeration. EIT can be performed at different cranio-caudal thoracic levels, but data are missing about the optimal belt position. The main goal of this prospective observational study was to evaluate the impact of different electrode layers on tidal impedance variation in relation to global volume changes in order to propose a proper belt position for EIT measurements. Methods: EIT measurements were performed in 15 mechanically ventilated intensive care patients with the electrode belt at different thoracic layers (L1-L7). All respiratory and hemodynamic parameters were recorded. Blood gas analyses were obtained once at the beginning of EIT examination. Off-line tidal impedance variation/tidal volume (TV/VT) ratio was calculated, and specific patterns of impedance distribution due to automatic and user-defined adjustment of the colour scale for EIT images were identified. Results: TV/VT ratio is the highest at L1. It decreases in caudal direction. At L5, the decrease of TV/VT ratio is significant. We could identify patterns of diaphragmatic interference with ventilation-related impedance changes, which owing to the automatically adjusted colour scales are not obvious in the regularly displayed EIT images. Conclusions: The clinical usability and plausibility of EIT measurements depend on proper belt position, proper impedance visualisation, correct analysis and data interpretation. When EIT is used to estimate global parameters like VT or changes in end-expiratory lung volume, the best electrode plane is between the 4th and 5th intercostal space. The specific colour coding occasionally suppresses user-relevant information, and manual rescaling of images is necessary to visualise this information.

Background: Critical illness following head injury is associated with a hypermetabolic state but there are insufficient epidemiological data describing acute nutrition delivery to this group of patients. Furthermore, there is little information describing relationships between nutrition and clinical outcomes in this population. Methods: We undertook an analysis of observational data, collected prospectively as part of International Nutrition Surveys 2007-2013, and extracted data obtained from critically ill patients with head trauma. Our objective was to describe global nutrition support practices in the first 12 days of hospital admission after head trauma, and to explore relationships between energy and protein intake and clinical outcomes. Data are presented as mean (SD), median (IQR), or percentages. Results: Data for 1045 patients from 341 ICUs were analyzed. The age of patients was 44.5 (19.7) years, 78 % were male, and median ICU length of stay was 13.1 (IQR 7.9-21.6) days. Most patients (94 %) were enterally fed but received only 58 % of estimated energy and 53 % of estimated protein requirements. Patients from an ICU with a feeding protocol had greater energy and protein intakes (p?<0.001, 0.002 respectively) and were more likely to survive (OR 0.65; 95 % CI 0.42-0.99; p?=?0.043) than those without. Energy or protein intakes were not associated with mortality. However, a greater energy and protein deficit was associated with longer times until discharge alive from both ICU and hospital (all p?<0.001). Conclusion: Nutritional deficits are commonplace in critically ill head-injured patients and these deficits are associated with a delay to discharge alive.

Background: Bleeding after cardiac surgery requiring surgical reexploration and blood component transfusion is associated with increased morbidity and mortality. Although prothrombin complex concentrate (PCC) has been used satisfactorily in bleeding disorders, studies on its efficacy and safety after cardiopulmonary bypass are limited. Methods: Between January 2005 and December 2013, 3454 consecutive cardiac surgery patients were included in an observational study aimed at investigating the efficacy and safety of PCC as first-line coagulopathy treatment as a replacement for fresh frozen plasma (FFP). Starting in January 2012, PCC was introduced as solely first-line treatment for bleeding following cardiac surgery. Results: After one-to-one propensity score–matched analysis, 225 pairs of patients receiving PCC (median dose 1500 IU) and FFP (median dose 2 U) were included. The use of PCC was associated with significantly decreased 24-h post-operative blood loss (836?±?1226 vs. 935?±?583 ml, p?<?0.0001). Propensity score–adjusted multivariate analysis showed that PCC was associated with significantly lower risk of red blood cell (RBC) transfusions (odds ratio [OR] 0.50; 95 % confidence interval [CI] 0.31–0.80), decreased amount of RBC units (? unstandardised coefficient ?1.42, 95 % CI ?2.06 to ?0.77) and decreased risk of transfusion of more than 2 RBC units (OR 0.53, 95 % CI 0.38–0.73). Patients receiving PCC had an increased risk of post-operative acute kidney injury (AKI) (OR 1.44, 95 % CI 1.02–2.05) and renal replacement therapy (OR 3.35, 95 % CI 1.13–9.90). Hospital mortality was unaffected by PCC (OR 1.51, 95 % CI 0.84–2.72). Conclusions: In the cardiac surgery setting, the use of PCC compared with FFP was associated with decreased post-operative blood loss and RBC transfusion requirements. However, PCC administration may be associated with a higher risk of post-operative AKI.

Background: Prolonged controlled mechanical ventilation depresses diaphragmatic efficiency. Assisted modes of ventilation should improve it. We assessed the impact of pressure support ventilation versus neurally adjusted ventilator assist on diaphragmatic efficiency.MethodPatients previously ventilated with controlled mechanical ventilation for 72 hours or more were randomized to be ventilated for 48 hours with pressure support ventilation (n =12) or neurally adjusted ventilatory assist (n?=?13). Neuro-ventilatory efficiency (tidal volume/diaphragmatic electrical activity) and neuro-mechanical efficiency (pressure generated against the occluded airways/diaphragmatic electrical activity) were measured during three spontaneous breathing trials (0, 24 and 48 hours). Breathing pattern, diaphragmatic electrical activity and pressure time product of the diaphragm were assessed every 4 hours. Results: In patients randomized to neurally adjusted ventilator assist, neuro-ventilatory efficiency increased from 27?±?19 ml/?V at baseline to 62?±?30 ml/?V at 48 hours (p?<0.0001) and neuro-mechanical efficiency increased from 1?±?0.6 to 2.6?±?1.1 cmH 2 O/?V (p?=?0.033). In patients randomized to pressure support ventilation, these did not change. Electrical activity of the diaphragm, neural inspiratory time, pressure time product of the diaphragm and variability of the breathing pattern were significantly higher in patients ventilated with neurally adjusted ventilatory assist. The asynchrony index was 9.48 [6.38– 21.73] in patients ventilated with pressure support ventilation and 5.39 [3.78– 8.36] in patients ventilated with neurally adjusted ventilatory assist (p?=?0.04). Conclusion: After prolonged controlled mechanical ventilation, neurally adjusted ventilator assist improves diaphragm efficiency whereas pressure support ventilation does not.Trial registrationClinicalTrials.gov study registration: NCT0247317, 06/11/2015.

Background: The aim of extracorporeal albumin dialysis (ECAD) is to reduce endogenous toxins accumulating in liver failure. To date, ECAD is conducted mainly with the Molecular Adsorbents Recirculating System (MARS). However, single-pass albumin dialysis (SPAD) has been proposed as an alternative. The aim of this study was to compare the two devices with a prospective, single-centre, non-inferiority crossover study design with particular focus on reduction of bilirubin levels (primary endpoint) and influence on paraclinical and clinical parameters (secondary endpoints) associated with liver failure. Methods: Patients presenting with liver failure were screened for eligibility and after inclusion were randomly assigned to be started on either conventional MARS or SPAD (with 4 % albumin and a dialysis flow rate of 700 ml/h). Statistical analyses were based on a linear mixed-effects model. Results: Sixty-nine crossover cycles of ECAD in 32 patients were completed. Both systems significantly reduced plasma bilirubin levels to a similar extent (MARS: median ?68 ?mol/L, interquartile range [IQR] ?107.5 to ?33.5, p?=?0.001; SPAD: ?59 ?mol/L, ?84.5 to +36.5, p?=?0.001). However, bile acids (MARS: ?39 ?mol/L, ?105.6 to ?8.3, p?<?0.001; SPAD: ?9 ?mol/L, ?36.9 to +11.4, p?=?0.131), creatinine (MARS: ?24 ?mol/L, ?46.5 to ?8.0, p?<?0.001; SPAD: ?2 ?mol/L, ?9.0 to +7.0/L, p?=?0.314) and urea (MARS: ?0.9 mmol/L, ?1.93 to ?0.10, p?=?0.024; SPAD: ?0.1 mmol/L, ?1.0 to +0.68, p?=?0.523) were reduced and albumin-binding capacity was increased (MARS: +10 %, ?0.8 to +20.9 %, p?<?0.001; SPAD: +7 %, ?7.5 to +15.5 %, p?=?0.137) only by MARS. Cytokine levels of interleukin (IL)-6 and IL-8 and hepatic encephalopathy were altered by neither MARS nor SPAD. Conclusions: Both procedures were safe for temporary extracorporeal liver support. While in clinical practice routinely assessed plasma bilirubin levels were reduced by both systems, only MARS affected other paraclinical parameters (i.e., serum bile acids, albumin-binding capacity, and creatinine and urea levels). Caution should be taken with regard to metabolic derangements and electrolyte disturbances, particularly in SPAD using regional citrate anti-coagulation.Trial registrationGerman Clinical Trials Register (www.drks.de) DRKS00000371. Registered 8 April 2010.

No abstract available

Objective: To compare elderly (? 80 yr), older (65–79 yr), and younger (< 65 yr) ICU admissions in Scotland in relation to trends in admission rates, regional variation in admissions, ICU treatment intensity, and ICU and 1-year mortality. Design: National 5-year cohort study of ICU first admissions (January 1, 2005, to December 31, 2009). Setting: All admissions to ICUs and combined units (level 2/3 care) in Scotland captured by the Scottish Intensive Care Society Audit Group database, linked with hospital discharge data and death records. Patients: A total of 40,142 patients: 3,865 were 80 years old or older (9.6%), 13,904 (34.6%) were 65–79 years old; and 22,373 were younger than 65 years (55.7%). Interventions: None. Measurements and Main Results: Between 2005 and 2009, elderly admission rates decreased from 36.6/10,000 (95% CI, 34.0–39.2) in 2005 to 28.7/10,000 (95% CI, 26.5–30.9) in 2009 (p < 0.001; relative decrease, 22.0%); older admission rates also decreased, but less steeply (31.1 [95% CI, 29.9–32.2] to 26.1 [95% CI, 25.1–27.1] per 10,000 population; p < 0.001; relative decrease, 16.1%). Rates were static for younger patients. Restricted to mechanically ventilated elderly patients, rates ranged from 13.9 to 30.1/10,000 between healthboard administrative regions (p < 0.001). Emergency surgical diagnoses were more prevalent for elderly patients (elderly, 39.8%; older, 25.1%; younger, 20.3%; p < 0.001). Subgroup analyses limited to pneumonia admissions (elderly, n = 242; older, n = 1,226; younger, n = 1,836) indicated similar acute physiology scores, but fewer preexisting comorbidities among elderly patients (p = 0.007), who received a shorter duration of organ support and ICU stay. Mortality rates were higher in elderly patients at ICU discharge (elderly, 26.5%; older, 25.0%; younger, 17.0%; p < 0.001; confounder adjusted odds ratio elderly vs younger, 2.33 [95% CI, 2.11–2.58]; p < 0.001). Differences persisted at 1 year (elderly, 52.2%; older, 43.8%; younger, 27.6%; adjusted odds ratio elderly vs younger, 3.72 [95% CI, 3.42–4.06]; p < 0.001). Conclusions: In Scotland, elderly and older ICU admission rates are decreasing, with regional geographic variation. Although limited by an absence of a measure of frailty, patient characteristics and treatment intensity suggest selection of less comorbid elderly patients, indicating possible rationing based on chronologic age.

Objectives: To identify a pediatric ventilator-associated condition definition for use in neonates and children by exploring whether potential ventilator-associated condition definitions identify patients with worse outcomes. Design: Retrospective cohort study and a matched cohort analysis. Setting: Pediatric, cardiac, and neonatal ICUs in five U.S. hospitals. Patients: Children 18 years old or younger ventilated for at least 1 day. Interventions: None. Measurements and Main Results: We evaluated the evidence of worsening oxygenation via a range of thresholds for increases in daily minimum fraction of inspired oxygen (by 0.20, 0.25, and 0.30) and daily minimum mean airway pressure (by 4, 5, 6, and 7?cm H2O). We required worsening oxygenation be sustained for at least 2 days after at least 2 days of stability. We matched patients with a ventilator-associated condition to those without and used Cox proportional hazard models with frailties to examine associations with hospital mortality, hospital and ICU length of stay, and duration of ventilation. The cohort included 8,862 children with 10,209 hospitalizations and 77,751 ventilator days. For the fraction of inspired oxygen 0.25/mean airway pressure 4 definition (i.e., increase in minimum daily fraction of inspired oxygen by 0.25 or mean airway pressure by 4), rates ranged from 2.9 to 3.2 per 1,000 ventilator days depending on ICU type; the fraction of inspired oxygen 0.30/mean airway pressure 7 definition yielded ventilator-associated condition rates of 1.1–1.3 per 1,000 ventilator days. All definitions were significantly associated with greater risk of hospital death, with hazard ratios ranging from 1.6 (95% CI, 0.7–3.4) to 6.8 (2.9–16.0), depending on thresholds and ICU type. Each definition was associated with prolonged hospitalization, time in ICU, and duration of ventilation, among survivors. The advisory board of the study proposed using the fraction of inspired oxygen 0.25/mean airway pressure 4 thresholds to identify pediatric ventilator-associated conditions in ICUs. Conclusions: Pediatric patients with ventilator-associated conditions are at substantially higher risk for mortality and morbidity across ICUs, regardless of thresholds used. Next steps include identification of risk factors, etiologies, and preventative measures for pediatric ventilator-associated conditions.

Objective: Selective vasopressin V1A receptor agonists may have advantages over arginine vasopressin in the treatment of septic shock. We compared the effects of selepressin, a selective V1A receptor agonist, arginine vasopressin, and norepinephrine on hemodynamics, organ function, and survival in an ovine septic shock model. Design: Randomized animal study. Setting: University hospital animal research laboratory. Subjects: Forty-six adult female sheep. Interventions: Fecal peritonitis was induced in the anesthetized, mechanically ventilated, fluid-resuscitated sheep, and they were randomized in two successive phases. Three late-intervention groups (each n = 6) received IV selepressin (1 pmol/kg/min), arginine vasopressin (0.25 pmol [0.1 mU]/kg/min), or norepinephrine (3 nmol [0.5 ?g]/kg/min) when mean arterial pressure remained less than 70?mm Hg despite fluid challenge; study drugs were thereafter titrated to keep mean arterial pressure at 70–80?mm Hg. Three early-intervention groups (each n = 7) received selepressin, arginine vasopressin, or norepinephrine at the same initial infusion rates as for the late intervention, but already when mean arterial pressure had decreased by 10% from baseline; doses were then titrated as for the late intervention. A control group (n = 7) received saline. All animals were observed until death or for a maximum of 30 hours. Measurements and Main Results: In addition to hemodynamic and organ function assessment, plasma interleukin-6 and nitrite/nitrate levels were measured. In the late-intervention groups, selepressin delayed the decrease in mean arterial pressure and was associated with lower lung wet/dry weight ratios than in the other two groups. In the early-intervention groups, selepressin maintained mean arterial pressure and cardiac index better than arginine vasopressin or norepinephrine, slowed the increase in blood lactate levels, and was associated with less lung edema, lower cumulative fluid balance, and lower interleukin-6 and nitrite/nitrate levels. Selepressin-treated animals survived longer than the other animals. Conclusions: In this clinically relevant model, selepressin, a selective V1A receptor agonist, was superior to arginine vasopressin and to norepinephrine in the treatment of septic shock, especially when administered early.

Objective: The open lung approach is a mechanical ventilation strategy involving lung recruitment and a decremental positive end-expiratory pressure trial. We compared the Acute Respiratory Distress Syndrome network protocol using low levels of positive end-expiratory pressure with open lung approach resulting in moderate to high levels of positive end-expiratory pressure for the management of established moderate/severe acute respiratory distress syndrome. Design: A prospective, multicenter, pilot, randomized controlled trial. Setting: A network of 20 multidisciplinary ICUs. Patients: Patients meeting the American-European Consensus Conference definition for acute respiratory distress syndrome were considered for the study. Interventions: At 12-36 hours after acute respiratory distress syndrome onset, patients were assessed under standardized ventilator settings (FIO2?0.5, positive end-expiratory pressure ?10 cm H2O). If Pao2/FIO2 ratio remained less than or equal to 200 mm Hg, patients were randomized to open lung approach or Acute Respiratory Distress Syndrome network protocol. All patients were ventilated with a tidal volume of 4 to 8 ml/kg predicted body weight. Measurements and Main Results: From 1,874 screened patients with acute respiratory distress syndrome, 200 were randomized: 99 to open lung approach and 101 to Acute Respiratory Distress Syndrome network protocol. Main outcome measures were 60-day and ICU mortalities, and ventilator-free days. Mortality at day-60 (29% open lung approach vs. 33% Acute Respiratory Distress Syndrome Network protocol, p = 0.18, log rank test), ICU mortality (25% open lung approach vs. 30% Acute Respiratory Distress Syndrome network protocol, p = 0.53 Fisher’s exact test), and ventilator-free days (8 [0-20] open lung approach vs. 7 [0-20] d Acute Respiratory Distress Syndrome network protocol, p = 0.53 Wilcoxon rank test) were not significantly different. Airway driving pressure (plateau pressure - positive end-expiratory pressure) and PaO2/FIO2 improved significantly at 24, 48 and 72 hours in patients in open lung approach compared with patients in Acute Respiratory Distress Syndrome network protocol. Barotrauma rate was similar in both groups. Conclusions: In patients with established acute respiratory distress syndrome, open lung approach improved oxygenation and driving pressure, without detrimental effects on mortality, ventilator-free days, or barotrauma. This pilot study supports the need for a large, multicenter trial using recruitment maneuvers and a decremental positive end-expiratory pressure trial in persistent acute respiratory distress syndrome.

Objectives: There is a marked propensity for patients with acetaminophen-induced acute liver failure to develop sepsis, which may culminate in multiple organ failure and death. Toll-like receptors sense pathogens and induce inflammatory responses, but whether this is protective or detrimental in acetaminophen-induced acute liver failure remains unknown. Design, Setting, and Patients: We assessed Toll-like receptor expression on circulating neutrophils and their function in 24 patients with acetaminophen-induced acute liver failure and compared with 10 healthy controls. Interventions: Neutrophil Toll-like receptor 2, -4, and -9 expression and cytokine production and function were studied ex vivo at baseline and following stimulation with lipopolysaccharide, oligodeoxynucleotides, ammonium chloride, and interleukin-8. To examine the influence of acetaminophen-induced acute liver failure plasma and endogenous DNA on Toll-like receptors-9 expression, healthy neutrophils were incubated with acetaminophen-induced acute liver failure plasma with and without deoxyribonuclease-I. Measurements and Main Results: Circulating neutrophil Toll-like receptor 9 expression was increased in acetaminophen-induced acute liver failure on day 1 compared with healthy controls (p = 0.0002), whereas Toll-like receptor 4 expression was decreased compared with healthy controls (p < 0.0001). Toll-like receptor 2 expression was unchanged. Neutrophil phagocytic activity was decreased, and spontaneous oxidative burst increased in all patients with acetaminophen-induced acute liver failure compared with healthy controls (p < 0.0001). Neutrophil Toll-like receptor 9 expression correlated with plasma interleukin-8 and peak ammonia concentration (r = 0.6; p < 0.05) and increased with severity of hepatic encephalopathy (grade 0–2 vs 3/4) and systemic inflammatory response syndrome score (0–1 vs 2–4) (p < 0.05). Those patients with advanced hepatic encephalopathy (grade 3/4) or high systemic inflammatory response syndrome score (2–4) on day 1 had higher neutrophil Toll-like receptor 9 expression, arterial ammonia concentration, and plasma interleukin-8 associated with neutrophil exhaustion. Healthy neutrophil Toll-like receptor 9 expression increased upon stimulation with acetaminophen-induced acute liver failure plasma, which was abrogated by preincubation with deoxyribonuclease-I. Intracellular Toll-like receptor 9 was induced by costimulation with interleukin-8 and ammonia. Conclusion: These data point to neutrophil Toll-like receptor 9 expression in acetaminophen-induced acute liver failure being mediated both by circulating endogenous DNA as well as ammonia and interleukin-8 in a synergistic manner inducing systemic inflammation, neutrophil exhaustion, and exacerbating hepatic encephalopathy.

Objective: To identify whether delays in rapid response team activation contributed to worse patient outcomes (mortality and morbidity). Design: Retrospective observational cohort study including all rapid response team activations in 2012. Setting: Tertiary academic medical center. Patients: All those 18 years old or older who had a rapid response team call activated. Vital sign data were abstracted from individual patient electronic medical records for the 24 hours before the rapid response team activation took place. Patients were considered to have a delayed rapid response team activation if more than 1 hour passed between the first appearance in the record of an abnormal vital sign meeting rapid response team criteria and the activation of an rapid response team. Interventions: None. Measurements and Main Results: A total of 1,725 patients were included in the analysis. Data were compared between those who had a delayed rapid response team activation and those who did not. Fifty seven percent patients met the definition of delayed rapid response team activation. Patients in high-frequency physiologic monitored environments were more likely to experience delay than their floor counterparts. In the no-delay group, the most common reasons for rapid response team activation were tachycardia/bradycardia at 29% (217/748), respiratory distress/low SpO2 at 28% (213/748), and altered level of consciousness at 23% (170/748) compared with respiratory distress/low SpO2 at 43% (423/977), tachycardia/bradycardia at 33% (327/977), and hypotension at 27% (261/977) in the delayed group. The group with no delay had a higher proportion of rapid response team calls between 8:00 and 16:00, whereas those with delay had a higher proportion of calls between midnight and 08:00. The delayed group had higher hospital mortality (15% vs 8%; adjusted odds ratio, 1.6; p = 0.005); 30-day mortality (20% vs 13%; adjusted odds ratio, 1.4; p = 0.02); and hospital length of stay (7 vs 6 d; relative prolongation, 1.10; p = 0.02) compared with the no-delay group. Conclusions: Delays in rapid response team activation occur frequently and are independently associated with worse patient mortality and morbidity outcomes.

Objective: To characterize fentanyl population pharmacokinetics in patients with critical illness and identify patient characteristics associated with altered fentanyl concentrations. Design: Prospective cohort study. Setting: Medical and surgical ICUs in a large tertiary care hospital in the United States. Patients: Patients with acute respiratory failure and/or shock who received fentanyl during the first 5 days of their ICU stay. Measurements and Main Results: We collected clinical and hourly drug administration data and measured fentanyl concentrations in plasma collected once daily for up to 5 days after enrollment. Among 337 patients, the mean duration of infusion was 58 hours at a median rate of 100 ?g/hr. Using a nonlinear mixed-effects model implemented by NONMEM, we found that fentanyl pharmacokinetics were best described by a two-compartment model in which weight, severe liver disease, and congestive heart failure most affected fentanyl concentrations. For a patient population with a mean weight of 92?kg and no history of severe liver disease or congestive heart failure, the final model, which performed well in repeated 10-fold cross-validation, estimated total clearance, intercompartmental clearance (Q), and volumes of distribution for the central (V1) and peripheral compartments (V2) to be 35?L/hr (95% CI, 32–39?L/hr), 55?L/hr (95% CI, 42–68?L/hr), 203?L (95% CI, 140–266?L), and 523?L (95% CI, 428–618?L), respectively. Severity of illness was marginally associated with fentanyl pharmacokinetics but did not improve the model fit after liver and heart diseases were included. Conclusions: In this study, fentanyl pharmacokinetics during critical illness were strongly influenced by severe liver disease, congestive heart failure, and weight, factors that should be considered when dosing fentanyl in the ICU. Future studies are needed to determine if data-driven fentanyl dosing algorithms can improve outcomes for ICU patients.

Objective: To evaluate the independent association between low peak admission plasma creatinine concentrations and in-hospital mortality in patients requiring critical care in Australia and New Zealand. Design: Multicenter, binational, retrospective cohort study. Setting: Data were extracted from the Australian and New Zealand Intensive Care Society Centre for Outcome and Resource Evaluation adult patient database. Patients: All available records for the period 2000 to 2013 were utilized. The following exclusion criteria were applied: all readmission episodes (within the same hospital stay), missing in-hospital mortality, admission post kidney transplantation, chronic renal replacement therapy (hemodialysis or peritoneal dialysis), and missing peak plasma creatinine concentration. Demographic, anthropometric, admission, illness severity, laboratory, and outcome data were then extracted. Patients were categorized on the basis of their peak (maximum) plasma creatinine concentration recorded in the first 24 hours of ICU admission. Illness severity–adjusted associations with in-hospital mortality relative to a reference category of 70–79 ?mol/L were then determined using multivariate logistic regression. Interventions: Nil. Measurements and Main Results: Data pertaining to 1,250,449 admissions were available for the study period. Following exclusions, 1,045,718 patients were included. Regression analysis identified that peak plasma creatinine concentrations less than 60 ?mol/L measured in the first 24 hours after ICU admission imply a steadily increasing adjusted in-hospital mortality risk. In cases where this value is markedly low (< 30 ?mol/L), the adjusted odds of dying in-hospital is over two-fold higher than the reference category and exceeds the risk implied with elevated (? 180 ?mol/L) values. This finding was also independent of anthropometric data. Conclusions: In a large heterogenous cohort of critically ill patients, low admission peak plasma creatinine concentrations are independently associated with increased risk-adjusted in-hospital mortality. Further research should now focus on the potential mechanisms underpinning this finding, such as a low skeletal muscle mass and/or fluid overload.