Biochar and compost from cotton residues inconsistently affect water use efficiency, nodulation, and growth of legumes under arid conditions.

There is an urgent global need to expand crop cultivation into arid and semiarid lands to guarantee food security. Thus, limited irrigation strategies and soil amendments are promising strategies for conserving water in arid and semi-arid crop production. Soil amendments, such as compost and biochar can improve soil water relationships, nitrogen (N) fixation, soil fertility, and crop productivity. A study was designed to evaluate the effect of biochar and compost applications on soil water relationships, nutrient uptake, plant growth, and N-fixation. A greenhouse pot experiment was conducted in two soils using a complete factorial design. The main effect, i.e., water content of each soil, was maintained at either 40% or 60% water filled porosity. The sub-effect, organic amendment type, was applied as biochar or compost. The sub-sub effect was rate of application (0, 5, and 10 Mg ha-1). Plant height and root length were significantly affected by the rate of amendment applied, whereas shoot and root mass differences were explained by irrigation strategy. Whole plant N uptake was moderately affected by water content only (p = 0.0818). Phosphorus and Potassium uptake were highly affected by amendment type and rate. Biochar moderately improved plant available water (0.061 %Vol Mg-1 ha-1) over the range of 0-20 Mg ha-1 in the sandier soil. Compost did not improve plant available water in either soil. Nodulation was affected by soil type only. The benefits of biochar or compost for plant were inconsistent and depended upon irrigation strategies, soil type, application rate, and plant species.

A Post Hoc Analysis of Osmotherapy Use in the Erythropoietin in Traumatic Brain Injury Study-Associations With Acute Kidney Injury and Mortality.

OBJECTIVES: Mannitol and hypertonic saline are used to treat raised intracerebral pressure in patients with traumatic brain injury, but their possible effects on kidney function and mortality are unknown. DESIGN: A post hoc analysis of the erythropoietin trial in traumatic brain injury (ClinicalTrials.gov NCT00987454) including daily data on mannitol and hypertonic saline use. SETTING: Twenty-nine university-affiliated teaching hospitals in seven countries. PATIENTS: A total of 568 patients treated in the ICU for 48 hours without acute kidney injury of whom 43 (7%) received mannitol and 170 (29%) hypertonic saline. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We categorized acute kidney injury stage according to the Kidney Disease Improving Global Outcome classification and defined acute kidney injury as any Kidney Disease Improving Global Outcome stage-based changes from the admission creatinine. We tested associations between early (first 2 d) mannitol and hypertonic saline and time to acute kidney injury up to ICU discharge and death up to 180 days with Cox regression analysis. Subsequently, acute kidney injury developed more often in patients receiving mannitol (35% vs 10%; p < 0.001) and hypertonic saline (23% vs 10%; p < 0.001). On competing risk analysis including factors associated with acute kidney injury, mannitol (hazard ratio, 2.3; 95% CI, 1.2-4.3; p = 0.01), but not hypertonic saline (hazard ratio, 1.6; 95% CI, 0.9-2.8; p = 0.08), was independently associated with time to acute kidney injury. In a Cox model for predicting time to death, both the use of mannitol (hazard ratio, 2.1; 95% CI, 1.1-4.1; p = 0.03) and hypertonic saline (hazard ratio, 1.8; 95% CI, 1.02-3.2; p = 0.04) were associated with time to death. CONCLUSIONS: In this post hoc analysis of a randomized controlled trial, the early use of mannitol, but not hypertonic saline, was independently associated with an increase in acute kidney injury. Our findings suggest the need to further evaluate the use and choice of osmotherapy in traumatic brain injury.

Erythropoietin in traumatic brain injury associated acute kidney injury: A randomized controlled trial.

BACKGROUND: Acute kidney injury (AKI) in traumatic brain injury (TBI) is poorly understood and it is unknown if it can be attenuated using erythropoietin (EPO). METHODS: Pre-planned analysis of patients included in the EPO-TBI (ClinicalTrials.gov NCT00987454) trial who were randomized to weekly EPO (40 000 units) or placebo (0.9% sodium chloride) subcutaneously up to three doses or until intensive care unit (ICU) discharge. Creatinine levels and urinary output (up to 7 days) were categorized according to the Kidney Disease Improving Global Outcome (KDIGO) classification. Severity of TBI was categorized with the International Mission for Prognosis and Analysis of Clinical Trials in TBI. RESULTS: Of 3348 screened patients, 606 were randomized and 603 were analyzed. Of these, 82 (14%) patients developed AKI according to KDIGO (60 [10%] with KDIGO 1, 11 [2%] patients with KDIGO 2, and 11 [2%] patients with KDIGO 3). Male gender (hazard ratio [HR] 4.0 95% confidence interval [CI] 1.4-11.2, P = 0.008) and severity of TBI (HR 1.3 95% CI 1.1-1.4, P < 0.001 for each 10% increase in risk of poor 6 month outcome) predicted time to AKI. KDIGO stage 1 (HR 8.8 95% CI 4.5-17, P < 0.001), KDIGO stage 2 (HR 13.2 95% CI 3.9-45.2, P < 0.001) and KDIGO stage 3 (HR 11.7 95% CI 3.5-39.7, P < 0.005) predicted time to mortality. EPO did not influence time to AKI (HR 1.08 95% CI 0.7-1.67, P = 0.73) or creatinine levels during ICU stay (P = 0.09). CONCLUSIONS: Acute kidney injury is more common in male patients and those with severe compared to moderate TBI and appears associated with worse outcome. EPO does not prevent AKI after TBI.

Permissive Underfeeding or Standard Enteral Feeding in Critically Ill Adults.

BACKGROUND: The appropriate caloric goal for critically ill adults is unclear. We evaluated the effect of restriction of nonprotein calories (permissive underfeeding), as compared with standard enteral feeding, on 90-day mortality among critically ill adults, with maintenance of the full recommended amount of protein in both groups. METHODS: At seven centers, we randomly assigned 894 critically ill adults with a medical, surgical, or trauma admission category to permissive underfeeding (40 to 60% of calculated caloric requirements) or standard enteral feeding (70 to 100%) for up to 14 days while maintaining a similar protein intake in the two groups. The primary outcome was 90-day mortality. RESULTS: Baseline characteristics were similar in the two groups; 96.8% of the patients were receiving mechanical ventilation. During the intervention period, the permissive-underfeeding group received fewer mean (±SD) calories than did the standard-feeding group (835±297 kcal per day vs. 1299±467 kcal per day, P<0.001; 46±14% vs. 71±22% of caloric requirements, P<0.001). Protein intake was similar in the two groups (57±24 g per day and 59±25 g per day, respectively; P=0.29). The 90-day mortality was similar: 121 of 445 patients (27.2%) in the permissive-underfeeding group and 127 of 440 patients (28.9%) in the standard-feeding group died (relative risk with permissive underfeeding, 0.94; 95% confidence interval [CI], 0.76 to 1.16; P=0.58). No serious adverse events were reported; there were no significant between-group differences with respect to feeding intolerance, diarrhea, infections acquired in the intensive care unit (ICU), or ICU or hospital length of stay. CONCLUSIONS: Enteral feeding to deliver a moderate amount of nonprotein calories to critically ill adults was not associated with lower mortality than that associated with planned delivery of a full amount of nonprotein calories. (Funded by the King Abdullah International Medical Research Center; PermiT Current Controlled Trials number, ISRCTN68144998.).

Permissive Underfeeding or Standard Enteral Feeding in High- and Low-Nutritional-Risk Critically Ill Adults. Post Hoc Analysis of the PermiT Trial.

RATIONALE: The optimal nutritional strategy for critically ill adults at high nutritional risk is unclear. OBJECTIVES: To examine the effect of permissive underfeeding with full protein intake compared with standard feeding on 90-day mortality in patients with different baseline nutritional risk. METHODS: This is a post hoc analysis of the PermiT (Permissive Underfeeding versus Target Enteral Feeding in Adult Critically Ill Patients) trial. MEASUREMENTS AND MAIN RESULTS: Nutritional risk was categorized by the modified Nutrition Risk in Critically Ill score, with high nutritional risk defined as a score of 5-9 and low nutritional risk as a score of 0-4. Additional analyses were performed by categorizing patients by body mass index, prealbumin, transferrin, phosphate, urinary urea nitrogen, and nitrogen balance. Based on the Nutrition Risk in Critically Ill score, 378 of 894 (42.3%) patients were categorized as high nutritional risk and 516 of 894 (57.7%) as low nutritional risk. There was no association between feeding strategy and mortality in the two categories; adjusted odds ratio (aOR) of 0.84 (95% confidence interval [CI], 0.56-1.27) for high nutritional risk and 1.01 (95% CI, 0.64-1.61) for low nutritional risk (interaction P = 0.53). Findings were similar in analyses using other definitions, with the exception of prealbumin. The association of permissive underfeeding versus standard feeding and 90-day mortality differed when patients were categorized by baseline prealbumin level (≤0.10 g/L: aOR, 0.57 [95% CI, 0.31-1.05]; >0.10 and ≤0.15 g/L: aOR, 0.79 [95% CI, 0.42-1.48]; >0.15 g/L: aOR, 1.55 [95% CI, 0.80, 3.01]; interaction P = 0.009). CONCLUSIONS: Among patients with high and low nutritional risk, permissive underfeeding with full protein intake was associated with similar outcomes as standard feeding.

The association of duration of boarding in the emergency room and the outcome of patients admitted to the intensive care unit.

BACKGROUND: The demand for critical care beds is increasing out of proportion to bed availability. As a result, some critically ill patients are kept in the Emergency Department (ED boarding) awaiting bed availability. The aim of our study is to examine the impact of boarding in the ED on the outcome of patients admitted to the Intensive Care Unit(ICU). METHODS: This was a retrospective analysis of ICU data collected prospectively at King Abdulaziz Medical City, Riyadh from ED between January 2010 and December 2012 and all patients admitted during this time were evaluated for their duration of boarding. Patients were stratified into three groups according to the duration of boarding from ED. Those admitted less than 6 h were classified as Group I, between 6 and 24 h, Group II and more than 24 h as Group III. We carried out multivariate analysis to examine the independent association of boarding time with the outcome adjusting for variables like age, sex, APACHE, Mechanical ventilation, Creatinine, Platelets, INR. RESULTS: During the study period, 940 patients were admitted from the ED to ICU, amongst whom 227 (25%) were admitted to ICU within 6 h, 358 (39%) within 6-24 h and 355 (38%) after 24 h. Patients admitted to ICU within 6 h were younger [48.7 ± 22.2(group I) years, 50.6 ± 22.6 (group II), 58.2 ± 20.9 (group III) (P = 0.04)]with less mechanical ventilation duration[5.9 ± 8.9 days (Group I), 6.5 ± 8.1 (Group II) and 10.6 ± 10.5 (Group III), P = 0.04]. There was a significant increase in hospital mortality [51(22.5), 104(29.1), 132(37.2), P = 0.0006) and the ICU length of stay(LOS) [9.55 days (Group I), 9.8 (Group II) and 10.6 (Group III), (P = 0.002)] with increase in boarding duration. In addition, the delay in admission was an independent risk factor for ICU mortality(OR for group III vs group I is 1.90, P = 0.04) and hospital mortality(OR for group III vs Group I is 2.09, P = 0.007). CONCLUSION: Boarding in the ED is associated with higher mortality. This data highlights the importance of this phenomenon and suggests the need for urgent measures to reduce boarding and to improve patient flow.

Erythropoietin in traumatic brain injury (EPO-TBI): a double-blind randomised controlled trial.

BACKGROUND: Erythropoietin might have neurocytoprotective effects. In this trial, we studied its effect on neurological recovery, mortality, and venous thrombotic events in patients with traumatic brain injury. METHODS: Erythropoietin in Traumatic Brain Injury (EPO-TBI) was a double-blind, placebo-controlled trial undertaken in 29 centres (all university-affiliated teaching hospitals) in seven countries (Australia, New Zealand, France, Germany, Finland, Ireland, and Saudi Arabia). Within 24 h of brain injury, 606 patients were randomly assigned by a concealed web-based computer-generated randomisation schedule to erythropoietin (40,000 units subcutaneously) or placebo (0·9% sodium chloride subcutaneously) once per week for a maximum of three doses. Randomisation was stratified by severity of traumatic brain injury (moderate vs severe) and participating site. With the exception of designated site pharmacists, the site dosing nurses at all sites, and the pharmacists at the central pharmacy in France, all study personnel, patients, and patients' relatives were masked to treatment assignment. The primary outcome, assessed at 6 months by modified intention-to-treat analysis, was improvement in the patients' neurological status, summarised as a reduction in the proportion of patients with an Extended Glasgow Outcome Scale (GOS-E) of 1-4 (death, vegetative state, and severe disability). Two equally spaced preplanned interim analyses were done (after 202 and 404 participants were enrolled). This study is registered with ClinicalTrials.gov, number NCT00987454. FINDINGS: Between May 3, 2010, and Nov 1, 2014, 606 patients were enrolled and randomly assigned to erythropoietin (n=308) or placebo (n=298). Ten of these patients (six in the erythropoietin group and four in the placebo group) were lost to follow up at 6 months; therefore, data for the primary outcome analysis was available for 596 patients (302 in the erythropoietin group and 294 in the placebo group). Compared with placebo, erythropoietin did not reduce the proportion of patients with a GOS-E level of 1-4 (134 [44%] of 302 patients in the erythropoietin group vs 132 [45%] of 294 in the placebo group; relative risk [RR] 0·99 [95% CI 0·83-1·18], p=0·90). In terms of safety, erythropoietin did not significantly affect 6-month mortality versus placebo (32 [11%] of 305 patients had died at 6 months in the erythropoietin group vs 46 [16%] of 297 [16%] in the placebo group; RR 0·68 [95% CI 0·44-1·03], p=0·07) or increase the occurrence of deep venous thrombosis of the lower limbs (48 [16%] of 305 vs 54 [18%] of 298; RR 0·87 [95% CI 0·61-1·24], p=0·44). INTERPRETATION: Following moderate or severe traumatic brain injury, erythropoietin did not reduce the number of patients with severe neurological dysfunction (GOS-E level 1-4) or increase the incidence of deep venous thrombosis of the lower limbs. The effect of erythropoietin on mortality remains uncertain. FUNDING: The National Health and Medical Research Council and the Transport Accident Commission.

Computerized physician order entry of a sedation protocol is not associated with improved sedation practice or outcomes in critically ill patients.

BACKGROUND: Computerized Physician Order Entry (CPOE) analgesia-sedation protocols may improve sedation practice and patients' outcomes. We aimed to evaluate the impact of the introduction of CPOE protocol. METHODS: This was a prospective, observational cohort study of adult patients receiving mechanical ventilation, requiring intravenous infusion of analgesics and/or sedatives, and expected to stay in the intensive care unit (ICU) ≥24 h. As a quality improvement project, the study had three phases: phase 1, no protocol, July 1st to September 30th, 2010; phase 2, post implementation of CPOE protocol, October 1st to December 31st, 2010; and phase 3, revised (age, kidney and liver function adjusted) CPOE protocol, August 1st to October 31st, 2011. Multivariate analyses were performed to determine the independent predictors of mortality. RESULTS: Two hundred seventy nine patients were included (no protocol = 91, CPOE protocol = 97, revised CPOE protocol = 91). Implementation of CPOE protocol was associated with increase of the average daily dose of fentanyl (3720 ± 3286 vs. 2647 ± 2212 mcg/day; p = 0.009) and decrease of hospital length of stay (40 ± 37 vs. 63 ± 85 days, p = 0.02). The revised CPOE protocol was associated with, compared to the CPOE protocol, a decrease of the average daily dose of fentanyl (2208 ± 2115 vs. 3720 ± 3286 mcg/day, p = 0.0002) and lorazepam (0 ± 0 vs. 0.06 ± 0.26 mg/day, p = 0.04), sedation-related complications during ICU stay (3.3 % vs. 29.9 %, p <0.0001), and ICU mortality (18 % vs. 39 %, p = 0.001). The impact of the revised CPOE protocol was more evident on patients aged >70 years or with severe kidney or liver impairment. Both the original CPOE protocol and the revised CPOE protocol were not independent predictors of ICU (adjusted odds ratio [aOR] = 1.85, confidence interval [CI] = 0.90-3.78; p = 0.09; aOR = 0.70, CI = 0.32-1.53, p = 0.37; respectively) or hospital mortality (aOR = 1.12, CI = 0.57-2.21, p = 0.74; aOR = 0.80, CI = 0.40-1.59, p = 0.52; respectively). CONCLUSIONS: The implementation of a CPOE analgesia-sedation protocol was not associated with improved sedation practices or patients' outcome but with unpredicted increases of an analgesic dose. However, the revised CPOE protocol (age, kidney and liver function adjusted) was associated with improved sedation practices. This study highlights the importance of carefully evaluating the impact of changes in practice to detect unanticipated outcomes.

Cardiorespiratory crisis at the end of pregnancy: a case of pheochromocytoma.

Pheochromocytoma during pregnancy is extremely rare. Its clinical manifestation includes hypertension with various clinical presentations, possibly resembling those of pregnancy-induced hypertension. The real challenge for clinicians is differentiating pheochromocytoma from other causes of hypertension (preeclampsia, gestational hypertension, and pre-existing or essential hypertension), from other cause of pulmonary edema (preeclampsia, peripartum cardiomyopathy, stress or Takotsubo cardiomyopathy, pre-existing cardiac disease [mitral stenosis], and high doses betamimetics), and from other causes of cardiovascular collapse (pulmonary embolism, and amniotic fluid embolism). Although, several cases of pheochromocytoma during pregnancy have been published, fetal and maternal mortalities due to undiagnosed cases are still reported. We report a case of a patient whose delivery by cesarean section was complicated by severe hemodynamic instability resulting in a cardiac arrest. Later on, pheochromocytoma was suspected based on computed tomography (CT) scan findings. Diagnosis was confirmed with special biochemical investigations that showed markedly elevated catecholamines in urine and metanephrines in serum, and later by histopathology of the excised left adrenal mass. This case illustrates the difficulty of diagnosing pheochromocytoma in pregnancy and raises the awareness to when this rare disease should be suspected.

[Chemotherapy-induced febrile neutropenia in a Tunisian Department of Pediatric Oncology]. / Neutropénie fébrile chimio-induite dans une unité d'oncologie pédiatrique tunisienne.

Chemotherapy-induced neutropenia (FN) is the most common infectious complication in pediatric oncology. To our knowledge, no pediatric research has been published in Tunisia. The purpose of our study was to describe the features of FN among Tunisian children and to investigate factors correlated with FN. We conducted a prospective study of children with chemotherapy-induced FN at the Department of Pediatric Medicine A of the Tunis Children´s Hospital from July 2019 to December 2019. We recorded 50 episodes of FN in 32 patients whose mean age was 5.3 years (3 months-16 years). We included 26 patients with solid tumors (81%) and six patients with hemopathies (18.7%). The mean time between last treatment and fever onset was 10.67 days. Bacteriological investigation was contributory in 18% of cases and mainly showed gram positive cocci. Therapeutic protocol including 1st line empirical antibiotic therapy (3rd generation cephalosporin with aminoglycoside) was effective in 62% of cases. Mortality rate of patients with FN was 2%. The statistical study did not reveal any factor of correlation with late-onset neutropenia. In conclusion, our results are consistent with literature data on bacteriological documentation and mortality. Our 1st line treatment option based on 3rd generation cephalosporin associated with aminoglycoside was effective in 2/3 of the cases. In the future, oral antibiotics may be considered in patients at low risk for infection.

Diagnostic challenge in a series of eleven patients with hyper IgE syndromes.

Hyper IgE syndromes (HIES) is a heterogeneous group of Inborn Errors of Immunity characterized by eczema, recurrent skin and lung infections associated with eosinophilia and elevated IgE levels. Autosomal dominant HIES caused by loss of function mutations in Signal transducer and activator of transcription 3 (STAT3) gene is the prototype of these disorders. Over the past two decades, advent in genetic testing allowed the identification of ten other etiologies of HIES. Although Dedicator of Cytokinesis 8 (DOCK8) deficiency is no more classified among HIES etiologies but as a combined immunodeficiency, this disease, characterized by severe viral infections, food allergies, autoimmunity, and increased risk of malignancies, shares some clinical features with STAT3 deficiency. The present study highlights the diagnostic challenge in eleven patients with the clinical phenotype of HIES in a resource-limited region. Candidate gene strategy supported by clinical features, laboratory findings and functional investigations allowed the identification of two heterozygous STAT3 mutations in five patients, and a bi-allelic DOCK8 mutation in one patient. Whole Exome Sequencing allowed to unmask atypical presentations of DOCK8 deficiency in two patients presenting with clinical features reminiscent of STAT3 deficiency. Our study underlies the importance of the differential diagnosis between STAT3 and DOCK8 deficiencies in order to improve diagnostic criteria and to propose appropriate therapeutic approaches. In addition, our findings emphasize the role of NGS in detecting mutations that induce overlapping phenotypes.

The role of an urban park's tree stand in shaping the enzymatic activity, glomalin content and physicochemical properties of soil.

Soil enzymes play a key role in the circulation of nutrients and the functioning of the ecosystem. The aim of the study was to assess how the tree species of urban agglomerations affect soil quality and enzymatic activity (dehydrogenases DEH, catalase CAT, alkaline AlP and acid AcP phosphatase, protease PR, ß-glucosidase GLU, and urease UR). To this end, soil samples were taken from beneath nine park trees. The risk of soil contamination by selected heavy metals (Pb, Ni, Cd) was also investigated against the background of the selected physicochemical properties. Enzyme activity results were used to calculate multi-parametric indices of soil quality: availability factor (AF), enzymatic pH indicator (AlP/AcP), biological index of fertility (BIF), geometric mean (GMea), alternation index (Al3), biochemical soil activity (BA16 and BA17). The results showed statistically significant differences in physicochemical and enzymatic properties of soil depending on tree species. Correlation analysis showed that the content of total organic carbon (TOC), total nirogen (TN), total phosphorus (TP) and humus (OM) in soil significantly influenced the activity of the studied enzymes and glomalin content. AF coefficient values (1.84%-18.19%) suggest that the bioavailability of available phosphorus (AP) was sufficient. The Pb, Ni, Cd content results were found to be low and did not exceed the permissible concentrations. DEH, CAT and AlP activity were highest under common hawthorn, and AcP, GLU and PR under northern white cedar. The calculated enzymatic indicators proved to be a sensitive and accurate indicator of the dynamics of changes taking place in the city park soil. Based on the results, an attempt can be made to assess the planning of sustainable development of studied areas of urban parks.

Sedation in ICU: are we achieving goals?

OBJECTIVE: The purpose of this study was to examine whether sedation goals, utilizing a validated sedation assessment scale, the Riker Sedation-Agitation Scale (SAS), and a standardized sedation protocol, were achieved in Intensive Care Unit (ICU) patients. DESIGN: This is a nested prospective cohort study SETTING: The study was conducted in a tertiary care medical-surgical ICU. PATIENTS: All mechanically ventilated adult patients who were judged by their treating intensivists to require intravenous sedation for more than 24 hours, were included in the study. INTERVENTIONS: A goal-directed protocol using the SAS was initiated following an educational program to the medical and nursing staff. MEASUREMENTS AND MAIN RESULTS: The following data was collected: patients' demographics, Acute Physiology and Chronic Health Evaluation (APACHE) II score, reason for admission, and outcome. For the first five ICU days, the bedside nurse documented ordered and average achieved SAS scores, every 4 hours. We compared the targeted versus achieved SAS scores using a paired Student's t-test. One hundred and five (105) patients were included in the study with mean age (+/-SD) of 47 (+/-23) and APACHE II (+/-SD) of 21 (+/-9). Achieved sedation scores were consistently lower than the requested goals during daytime and nighttime shifts throughout the study period. This did not change even after 3 months of implementing the protocol. CONCLUSION: Achieved levels of SAS score were consistently lower than what was requested by physicians despite an educational program and the use of a standardized protocol. Differences between targeted and achieved SAS scores persisted throughout the whole study period even three months after protocol implementation. These data suggest the need for alternative, more sensitive and precise approaches, to titrate sedation to targeted levels.

Caloric intake and the fat-to-carbohydrate ratio in hypercapnic acute respiratory failure: Post-hoc analysis of the PermiT trial.

BACKGROUND: The effect of moderate caloric enteral intake in critically ill patients with hypercapnic acute respiratory failure (HCARF) is unclear. We studied the impact of permissive underfeeding (PUF) compared with standard feeding (SF) on various HCARF outcomes. MATERIALS AND METHODS: The PermiT trial randomized 894 patients to either PUF (40-60% caloric requirement) or SF (70-100% requirement) with similar protein intake and found no difference in mortality, mechanical ventilation (MV) duration and ventilator-free days. In this post-hoc study, we restricted analysis to mechanically-ventilated patients with HCARF (PaCO2 >45 mmHg on the first two study days) and assessed the impact of trial interventions and fat-to-carbohydrate ratio on outcomes. RESULTS: One-hundred-twenty patients had HCARF (59 PUF and 61 SF, age 53.7 ± 17.8 years, body mass index 31.1 ± 11.2 kg/m2, Acute Physiology and Chronic Health Evaluation II score 21.7 ± 7.1 and day-1 PaCO2 61 ± 16 mmHg). Caloric intake was 815 ± 270 kcal/day in PUF group and 1289 ± 407 kcal/day in SF group. The two groups had similar PaCO2 levels during ICU stay. The 90-day mortality (33.9% versus 35.6%, p = 0.85), MV duration (10.7 ± 6.8 versus 11.1 ± 8.1 days, p = 0.56) and ventilator-free days (52.9 ± 38.6 versus 51.2 ± 38.0 days, p = 0.80) were also similar in PUF and SF groups, respectively. Ventilator-free days and 90-day mortality were similar when the fat-to-carbohydrate ratio was < or ≥ the median value (0.73) in all patients and in PUF and SF groups. CONCLUSIONS: In patients with HCARF, SF and PUF were associated with similar PaCO2, MV duration, ventilator-free days and mortality. Fat-to-carbohydrate ratio was not associated with mortality or ventilator-free days. TRIAL REGISTRATION: ISRCTN Registry: ISRCTN68144998.

Cost-Effectiveness of Erythropoietin in Traumatic Brain Injury: A Multinational Trial-Based Economic Analysis.

The EPO-TBI multi-national randomized controlled trial found that erythropoietin (EPO), when compared to placebo, did not affect 6-month neurological outcome, but reduced illness severity-adjusted mortality in patients with traumatic brain injury (TBI), making the cost-effectiveness of EPO in TBI uncertain. The current study uses patient-level data from the EPO-TBI trial to evaluate the cost-effectiveness of EPO in patients with moderate or severe TBI from the healthcare payers' perspective. We addressed the issue of transferability in multi-national trials by estimating costs and effects for specific geographical regions of the study (Australia/New Zealand, Europe, and Saudi Arabia). Unadjusted mean quality-adjusted life-years (QALYs; 95% confidence interval [CI]) at 6 months were 0.027 (0.020-0.034; p < 0.001) higher in the EPO group, with an adjusted QALY increment of 0.014 (0.000-0.028; p = 0.04). Mean unadjusted costs (95% CI) were $US5668 (-9191 to -2144; p = 0.002) lower in the treatment group; controlling for baseline IMPACT-TBI score and regional heterogeneity reduced this difference to $2377 (-12,446 to 7693; p = 0.64). For a willingness-to-pay threshold of $US50,000 per QALY, 71.8% of replications were considered cost-effective. Therefore, we did not find evidence that EPO was significantly cost-effective in the treatment of moderate or severe TBI at 6-month follow-up.

Intensive versus conventional insulin therapy: a randomized controlled trial in medical and surgical critically ill patients.

OBJECTIVE: The role of intensive insulin therapy in medical surgical intensive care patients remains unclear. The objective of this study was to examine the effect of intensive insulin therapy on mortality in medical surgical intensive care unit patients. DESIGN: Randomized controlled trial. SETTINGS: Tertiary care intensive care unit. PATIENTS: Medical surgical intensive care unit patients with admission blood glucose of > 6.1 mmol/L or 110 mg/dL. INTERVENTION: A total of 523 patients were randomly assigned to receive intensive insulin therapy (target blood glucose 4.4-6.1 mmol/L or 80-110 mg/dL) or conventional insulin therapy (target blood glucose 10-11.1 mmol/L or 180-200 mg/dL). MEASUREMENTS AND MAIN OUTCOMES: The primary end point was intensive care unit mortality. Secondary end points included hospital mortality, intensive care unit and hospital length of stay, mechanical ventilation duration, the need for renal replacement therapy and packed red blood cells transfusion, and the rates of intensive care unit acquired infections as well as the rate of hypoglycemia (defined as blood glucose < or = 2.2 mmol/L or 40 mg/dL). There was no significant difference in intensive care unit mortality between the intensive insulin therapy and conventional insulin therapy groups (13.5% vs. 17.1%, p = 0.30). After adjustment for baseline characteristics, intensive insulin therapy was not associated with mortality difference (adjusted hazard ratio 1.09, 95% confidence interval 0.70-1.72). Hypoglycemia occurred more frequently with intensive insulin therapy (28.6% vs. 3.1% of patients; p < 0.0001 or 6.8/100 treatment days vs. 0.4/100 treatment days; p < 0.0001). There was no difference between the intensive insulin therapy and conventional insulin therapy in any of the other secondary end points. CONCLUSIONS: Intensive insulin therapy was not associated with improved survival among medical surgical intensive care unit patients and was associated with increased occurrence of hypoglycemia. Based on these results, we do not advocate universal application of intensive insulin therapy in intensive care unit patients. TRIAL REGISTRATION: Current Controlled Trials registry (ISRCTN07413772) http://www.controlled-trials.com/ISRCTN07413772/07413772; 2005.

Tachyphylaxis to cisatracurium--case reports and literature review.

Nondepolarizing neuromuscular blocking agents (NNMBAs) are commonly used in the intensive care unit (ICU), mainly to facilitate mechanical ventilation in critically ill patients who are not responding to sedatives and analgesics alone. Tachyphylaxis, also referred to as resistance, may develop during long-term infusion of NNMBAs. Several case reports of tachyphylaxis to NNMBAs have been reported. Although the definite mechanisms of tachyphylaxis to NNMBAs are not clear, several pharmacodynamic and pharmacokinetic changes have been described with the development of resistance. Tachyphylaxis to NNMBAs is associated with adverse outcomes including inadequate ventilation, increased risk of dose-dependent side effects, and increased drug costs. Patients who develop tachyphylaxis to one NNMBA should be treated with another NNMBA if neuromuscular blockade (NMB) is still indicated. We report three cases of tachyphylaxis to cisatracurium in a surgical intensive care unit (SICU): one in patient with acute respiratory distress syndrome (ARDS) and the other two with traumatic brain injury (TBI).

Cause and Timing of Death and Subgroup Differential Effects of Erythropoietin in the EPO-TBI Study.

The EPO-TBI study randomized 606 patients with moderate or severe traumatic brain injury (TBI) to be treated with weekly epoetin alfa (EPO) or placebo. Six month mortality was lower in EPO treated patients in an analysis adjusting for TBI severity. Knowledge of possible differential effects by TBI injury subtype and acute neurosurgical treatment as well as timing and cause of death (COD) will facilitate the design of future interventional TBI trials. We defined COD as cerebral (brain death, cerebral death with withdrawal, or death during maximal care) and non-cerebral (death following withdrawal or during maximal care, which had a non-cerebral cause). The study included 305 patients treated with EPO and 297 treated with placebo, with COD recorded in 77 (99%) out of 78 non-survivors. Median time to death in patients dying of cerebral COD was 8 days (interquartile range [IQR] 5-16) compared with 29 days (IQR 7-56) (p = 0.01) for non-cerebral COD. When assessing subgroups by admission CT scan injury findings, we found no significant differential effects of EPO compared with placebo. However, EPO appeared more effective in patients with an injury type not requiring a neurosurgical operation prior to intensive care unit (ICU) admission (odds ratio [OR] 0.29, 95% confidence interval [CI] 0.14-0.61, p = 0.001, p for interaction = 0.003) and in this subgroup, fewer patients died of cerebral causes in the EPO than in the placebo group (5% compared with 14%, p = 0.03). In conclusion, most TBI deaths were from cerebral causes that occurred during the first 2 weeks, and were related to withdrawal of care. EPO appeared to specifically reduce cerebral deaths in the important subgroup of patients with a diffuse type of injury not requiring a neurosurgical intervention prior to randomization.

Changing sedation practices in the intensive care unit--protocol implementation, multifaceted multidisciplinary approach and teamwork.

INTRODUCTION: Sedation protocols have demonstrated effectiveness in improving ICU sedation practices. However, the importance of multifaceted multidisciplinary approach on the success of such protocols has not been fully examined. METHODS: The study was conducted in a tertiary care medical-surgical ICU as a prospective, 4-pronged, observational study describing a quality improvement initiative that employs 2 types of controlled comparisons: a "before and after" comparison related to intense education of ICU clinicians and nurses about sedation and analgesia in the ICU, and a comparison of protocolized versus non-protocolized care. Patients were assigned alternatively to receive sedation by a goal-directed protocol using the Riker Sedation-Agitation Scale (SAS) or by standard practice. A multifaceted multidisciplinary educational program was initiated including the use of point of use reminders, directed educational efforts, and opinion leaders. This included several lectures and in-services and the routine availability of at least one member of this group to answer questions. We included all consecutive patients receiving mechanical ventilation, who were judged by their treating team to require intravenous sedation. MEASUREMENTS AND MAIN RESULTS: The following data was collected: demographics, Acute Physiology and Chronic Health Evaluation (APACHE) II score and Simplified Acute Physiology score (SAPS) II, daily doses of analgesics and sedatives, duration of mechanical ventilation, ICU length of stay (LOS) and ventilator associated pneumonia (VAP) incidence. To examine the effect of the multifaceted multidisciplinary approach, we compared the first 3 months to the second 3 months in the following 4 groups: G1 no protocol group in the first 3 months, G2 protocol group in first 3 months, G3 no protocol group in the second 3 months, G4 protocol group in the second 3 months. After ICU day 3, SAS in the groups G2, G3 and G4 became higher than in G1 reflecting "lighter" levels of sedation. There were significant reductions in the use of analgesics and sedatives in the protocol group after 3 months. This was associated with a reduction in VAP rate and trends towards shorter mechanical ventilation duration and hospital length of stay (LOS). CONCLUSIONS: The implementation of a multifaceted multidisciplinary approach including the use of point of use reminders, directed educational efforts, and opinion leaders along with sedation protocol led to significant changes in sedation practices and improvement in patients' outcomes. Such approach appears to be critical for the success of ICU sedation protocol.

Erythropoietin in patients with traumatic brain injury and extracranial injury-A post hoc analysis of the erythropoietin traumatic brain injury trial.

BACKGROUND: Erythropoietin (EPO) may reduce mortality after traumatic brain injury (TBI). Secondary brain injury is exacerbated by multiple trauma, and possibly modifiable by EPO. We hypothesized that EPO decreases mortality more in TBI patients with multiple trauma, than in patients with TBI alone. METHODS: A post hoc analysis of the EPO-TBI randomized controlled trial conducted in 2009 to 2014. To evaluate the impact of injuries outside the brain, we calculated an extracranial Injury Severity Score (ISS) that included the same components of the ISS, excluding head and face components. We defined multiple trauma as two injured body regions with an Abbreviated Injury Scale (AIS) score of 3 or higher. Cox regression analyses, allowing for potential differential responses per the presence or absence of extracranial injury defined by these injury scores, were used to assess the effect of EPO on time to mortality. RESULTS: Of 603 included patients, the median extracranial ISS was 6 (interquartile range, 1-13) and 258 (43%) had an AIS score of 3 or higher in at least two body regions. On Cox regression, EPO was associated with decreased mortality in patients with greater extracranial ISS (interaction p = 0.048) and weakly associated with differential mortality with multiple trauma (AIS score > 3 or in two regions, interaction p = 0.17). At 6 months in patients with extracranial ISS higher than 6, 10 (6.8%) of 147 EPO-treated patients compared with 26 (17%) of 154 placebo-treated patients died (risk reduction, 10%; 95% confidence interval, 2.9-17%; p = 0.007). CONCLUSION: In this post hoc analysis, EPO administration was associated with a potential differential improvement in 6-month mortality in TBI patients with more severe extracranial injury. These findings need confirmation in future clinical and experimental studies. LEVEL OF EVIDENCE: Therapeutic study, level III.