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Critical Care Reviews Newsletter

April 21st 2013



Welcome to the 72nd Critical Care Reviews Newsletter, bringing you the best critical care research published in the past week, plus a wide range of free full text review articles and guidelines from over 300 clinical and scientific journals.

This has been a busy week for critical care research publications, with the headline study being the long awaited REDOXS trial, which unfortunately reports increased mortality with glutamine use, and no effect from anti-oxidants in the critically ill. Also, there are positive studies on selenium, linezolid, subglottic stenosis and copper surfaces for the prevention of hospital acquired infections and colonizations. Balancing this are negative studies, demonstrating a lack of efficacy of sodium bicarbonate for the prevention of post-operative acute kidney injury, and an interesting physiological study showing no increase in renal blood flow with a fluid bolus. The era of organogenesis slow approaches, with a report in Nature Medicine of a successfully engineered rat kidney.

There are a number of guidelines published this week, with the standout article being an updated version of the European haemorrhage guideline. Similarly, there are several commentaries, including discussions on mechanical ventilation, high frequency oscillation, H7N9 influenza and carbapenam resistant bacteria.

Amongst the clinical review articles are papers on septic encephalopathy, levosimendan, Takosubo cardiomyopathy, inhalation injury, rapid sequence induction, tissue engineering for small intestine and liver, protein requirements in the critically ill, thromboelastography, and a critical care update paper.

The topic for This Week's Papers is haematological disorders, starting with a paper on the porphyrias in tomorrow's Paper of the Day.



New England Journal of Medicine:     Pharmaconutrition

Heyland and colleagues performed a blinded 2-by-2 factorial trial in 1223 critically ill adults with multiorgan failure and receiving mechanical ventilation, to receive supplements of glutamine, antioxidants (selenium, zinc, beta carotene, vitamin E, and vitamin C), both, or placebo. Supplements were started within 24 hours after admission to the ICU and were provided both intravenously and enterally. Glutamine therapy was associated with a trend toward increased mortality at 28 days (32.4% vs. 27.2%; adjusted odds ratio, 1.28; 95% CI 1.00 - 1.64; p=0.05) and with increased in-hospital (37.2% versus 31.0, p=0.02) and 6 month mortality (43.7% versus 37.2%, p=0.02). Antioxidants had no effect on 28-day mortality (anti-oxidants 30.8%, versus no anti-oxidants 28.8%; adjusted odds ratio, 1.09; 95% CI 0.86 - 1.40; p=0.48) or any other secondary end point. There were no differences among the groups with respect to serious adverse events (P=0.83).

Abstract:  Heyland. A Randomized Trial of Glutamine and Antioxidants in Critically Ill Patients (REDOXS study). N Engl J Med 2013;368:1489-1497


PLoS Medicine:     Bicarbonate for Kidney Injury Prevention

Haase et al performed a multicenter, double-blind, randomized controlled trial in 350 adult patients undergoing open heart surgery with the use of cardiopulmonary bypass, comparing 24 hours of intravenous infusion of sodium bicarbonate (n=174, 5.1 mmol/kg) or sodium chloride (n=176, 5.1 mmol/kg) on the incidence of post-operative acute kidney injury. Secondary endpoints included the magnitude of acute tubular damage as measured by urinary neutrophil gelatinase-associated lipocalin (NGAL), initiation of acute renal replacement therapy, and mortality. The study was stopped early due to a likely lack of efficacy and possible harm. At baseline, a greater proportion of patients in the sodium bicarbonate group presented with preoperative chronic kidney disease compared to control (38% versus 25%; p = 0.009). Sodium bicarbonate therapy was associated with a higher incidence of AKI (47.7% versus 36.4%, odds ratio 1.60, 95% CI 1.04–2.45; unadjusted p = 0.032). After multivariable adjustment, a non-significant unfavorable group difference affecting patients receiving sodium bicarbonate was found for the primary endpoint (OR 1.45 [0.90–2.33], p = 0.120]). A greater postoperative increase in urinary NGAL in patients receiving bicarbonate infusion was observed compared to control patients (p = 0.011). The incidence of postoperative renal replacement therapy was similar but hospital mortality was increased in patients receiving sodium bicarbonate compared with control (6.3% versus 1.7%, OR 3.89 [1.07–14.2], p = 0.031).

Full Text:  Haase. Prophylactic Perioperative Sodium Bicarbonate to Prevent Acute Kidney Injury Following Open Heart Surgery: A Multicenter Double-Blinded Randomized Controlled Trial. PLoS Med 2013;10(4):e1001426


Intensive Care Medicine:     Hypothermia for Cardiac Arrest

Vaahersalo completed a prospective observational study evaluating all 548 adult out-of-hospital cardiac arrest (OHCA) patients admitted to 21 ICUs in Finland from March over a one year period.  311 patients (56.8%) had a shockable initial rhythm (incidence of 7.4/100,000/year) and 237 patients (43.2%) had a non-shockable rhythm (incidence of 5.6/100,000/year). At ICU admission, 504 (92%) patients were unconscious. Therapeutic hypothermia was given to 241/281 (85.8 %) unconscious patients resuscitated from shockable rhythms, with unfavourable 1-year neurological outcome (cerebral performance categories, CPC 3–4–5) in 42.0% with therapeutic hypothermia versus 77.5 % without therapeutic hypothermia (p < 0.001). Therapeutic hypothermia was given to 70/223 (31.4 %) unconscious patients resuscitated from non-shockable rhythms, with 1-year CPC of 3–4–5 in 80.6% (54/70) with therapeutic hypothermia versus 84.0 % (126/153) without therapeutic hypothermia (p = 0.56). This lack of difference remained after adjustment for propensity to receive therapeutic hypothermia in patients with non-shockable rhythms.

Abstract: Vaahersalo. Therapeutic hypothermia after out-of-hospital cardiac arrest in Finnish intensive care units: the FINNRESUSCI study. Intensive Care Med 2013;39(5):826-837   

Editorial:  Deye. To cool or not to cool non-shockable cardiac arrest patients: it is time for randomized controlled trials. Intensive Care Med 2013;39(5):966-969


Critical Care:     ECMO

Aubron and colleagues completed an analysis of a 5 year prospective ECMO database consisting of 158 ECMO therapies in 151 patients. Two thirds were treated with veno-arterial ECMO and one-third with veno-venous ECMO. VV ECMO was associated with a significantly shorter duration of ECMO (median/IQR: 7/5-10 versus 10/6-16) with over 70% of ECMO cases successfully weaned in each group.  The overall mortality was 37.3% (VA ECMO 37.1% and VV ECMO 37.7%). Haemorrhagic events, assessed by the total of red blood cells units received during ECMO were associated with hospital mortality for both ECMO types.

Full Text:  Aubron. Factors associated with outcomes of patients on extracorporeal membrane oxygenation support: a 5-year cohort study. Critical Care 2013;17:R73


Intensive Care Medicine:     ECMO

In 10 mechanically ventilated ARDS patients receiving femoro–jugular vv-ECMO blood gases and hemodynamic parameters were evaluated after changing one of three ECMO settings: circuit blood flow, FiO2ECMO (fraction of inspired oxygen in circuit), or sweep gas flow ventilating the membrane, while leaving the other two parameters at their maximum setting. Bood flow was the main determinant of arterial oxygenation, while CO2 elimination depended on sweep gas flow through the oxygenator. An ECMO flow/cardiac output >60 % was constantly associated with adequate blood oxygenation and oxygen transport and delivery.

Abstract: Schmidt. Blood oxygenation and decarboxylation determinants during venovenous ECMO for respiratory failure in adults. Intensive Care Med 2013;39(5):838-846


Critical Care:     Enoxaparin Dosing

Robinson et al completed a double-blind randomized controlled trial in 80 critically ill patients weighing 50 - 90 kilograms, comparing different regimes of subcutaneous (sc) enoxaparin: 40 mg once daily (QD), 30 mg twice daily (BID), 40mg BID, or 1mg/kg QD, each administered for three days. On day 1, mean peak anti-Xa levels were similar with 40 mg QD (n= 20, 0.20 IU/ml) and 40 mg BID (n=19, 0.17 IU/ml), lower with 30 mg BID (n= 20, 0.08 IU/ml) and higher with 1 mg/kg QD (n=19, 0.34 IU/ml). At steady state (day 3), mean peak anti-Xa levels were: 40 mg QD (0.13 IU/ml), 30 mg BID (0.15 IU/ml), 40 mg BID (0.33 IU/ml) and 1 mg/kg QD (0.40 IU/ml), with these difference being statistically significant (p <0.0001). Doses of 40 mg BID and 1mg/kg QD enoxaparin yielded target anti-Xa levels for over 80% of the study period. There were no adverse effects.

Robinson. A comparative study of varying doses of enoxaparin for thromboprophylaxis in critically ill patients: double-blinded, randomised controlled trial. Critical Care 2013;17:R75


Nature Medicine:     Renal Organogenesis

Song et al performed a proof-of-concept study, engineering a kidney and successfully transplanting into a rat. Rat, porcine and human kidneys were decellularized by detergent perfusion, yielding acellular scaffolds with vascular, cortical and medullary architecture, a collecting system and ureters. These scaffolds were seeded with rat epithelial and endothelial cells and perfused these cell-seeded constructs in a whole-organ bioreactor. The resulting grafts produced rudimentary urine in vitro when perfused through their intrinsic vascular bed. When transplanted in an orthotopic position in rat, the grafts were perfused by the recipient's circulation and produced urine through the ureteral conduit in vivo.

Abstract:  Song. Regeneration and experimental orthotopic transplantation of a bioengineered kidney. Nature Medicine 2013;epublished April 14th


British Journal of Anaesthesia:     Perioperative Anaphylaxis

Gibbs and colleagues analysed the 2000–2009 database of the West Australian Anaesthetic Mortality Committee for perioperative anaphylaxis events. From approximately 3 million anaesthetics there were 264 cases, giving a perioperative anaphylaxis rate of ∼1:11 000. There were no anaphylaxis-related deaths (95% CI: 0–1.4%).

Abstract:  Gibbs. Survival from perioperative anaphylaxis in Western Australia 2000–2009. Br J Anaesth 2013;epublished April 18th


Intensive Care Medicine:     Sedation

Shehabi et al conducted a multicentre prospective longitudinal cohort study in 259 patients sedated and mechanically ventilated ≥24 h. Midazolam was the main sedative prescribed. Adjusted multivariable Cox proportional hazard regression analysis showed that early deep sedation was independently associated with longer time to extubation (hazard ratio 0.93, 95% CI 0.89–0.97, p=0.003), increased hospital mortality (HR 1.11, 95 % CI 1.05–1.18, P < 0.001) and increased 180-day mortality (HR 1.09, 95 % CI 1.04–1.15, P = 0.002), but not time to delirium (HR 0.98, P = 0.23). Delirium occurred in 114 (44 %) of patients.

Full Text:  Shehabi. Sedation depth and long-term mortality in mechanically ventilated critically ill adults: a prospective longitudinal multicentre cohort study (SPICE study). Intensive Care Med 2013;39(5):910-918


Critical Care Medicine:     Outcomes post ICU

In a cohort study of 91,203 Dutch ICU survivors discharged alive from hospital, the mortality risk at 1, 2, and 3 years was 12.5%, 19.3%, and 27.5%, respectively. The 3-year mortality after hospital discharge in ICU patients was higher than the weighted average of the gender and age-specific death risks of the general Dutch population (27.5% versus 8.2%). In comparison with general ICU patients, elective and cardiac surgical patients had lower adjusted hazard ratios for mortality (0.73 and 0.28, respectively), while medical and cancer patients had higher adjusted hazard ratios for mortality (1.41, 1.94, respectively).

Abstract:  Brinkman. Mortality After Hospital Discharge in ICU Patients. Crit Care Med 2013;41(5):1229-1236


Critical Care Medicine:     ECMO in Cardiac Arrest

Maekawa et al perfomed a post hoc analysis of a Japanese prospective observational database to compare neurologic outcome following extracorporeal cardiopulmonary resuscitation (n=53) with conventional cardiopulmonary resuscitation (n=109) in adults with witnessed cardiac arrest of cardiac origin who had undergone cardiopulmonary resuscitation for longer than 20 minutes. Propensity score matching was used to reduce selection bias and balance the baseline characteristics and clinical variables that could potentially affect outcome (n=24 both groups). Intact survival rate was higher in the matched extracorporeal cardiopulmonary resuscitation group than in the matched conventional cardiopulmonary resuscitation group (29.2% [7/24] vs. 8.3% [2/24], log-rank p = 0.018). According to the predictor analysis, only pupil diameter on hospital arrival was associated with neurologic outcome (adjusted hazard ratio, 1.39 per 1-mm increase; 95%CI 1.09–1.78; p = 0.008).

Abstract:  Maekawa. Extracorporeal Cardiopulmonary Resuscitation for Patients With Out-of-Hospital Cardiac Arrest of Cardiac Origin: A Propensity-Matched Study and Predictor Analysis. Crit Care Med 2013;41(5):1186-1196


Critical Care Medicine:     Effects of Fluid Challenge on Renal Perfusion

Schnell and colleagues performed a prospective cohort study in 35 patients in 3 French ICUs to assess renal resistive index variations in response to fluid challenge. 17 (49%) were fluid responsive (had at least a 10% increase in aortic blood flow). After fluid challenge, mean arterial pressure increased from 73 mm Hg (IQR 68–79) to 80 mm Hg (75–86; p < 0.0001) and stroke volume from 50 mL (30–77) to 55 mL (39–84; p < 0.0001). Stroke volume changes after fluid challenge were +28.6% (+18.8% to +38.8%) in fluid challenge responders and +3.1% (–1.6% to 7.4%) in fluid challenge nonresponders. Renal resistive index was unchanged after fluid challenge in both nonresponders (0.72 [0.67–0.75] before and 0.71 [0.67–0.75] after fluid challenge; p = 0.62) and responders (0.70 [0.65–0.75] before and 0.72 [0.68–0.74] after fluid challenge; p = 0.11). Stroke volume showed no correlations with resistive index changes after fluid challenge in the overall population (r2 = 0.04, p = 0.25), in fluid challenge responders (r2 = –0.02, p = 0.61), or in fluid challenge nonresponders (r2 = 0.08, p = 0.27). Stroke volume did not correlate with resistive index changes after fluid challenge in the subgroups without acute kidney injury, with transient acute kidney injury, or with persistent acute kidney injury.

Abstract: Schnell. Renal Perfusion Assessment by Renal Doppler During Fluid Challenge in Sepsis. Crit Care Med 2013;41(5):1214-1220

Critical Care Medicine:     Selenium

Alhazzani and colleagues performed a systematic review and meta analysis to determine the efficacy and safety of high-dose selenium supplementation compared to placebo for the reduction of mortality in patients with sepsis. Nine trials (n=792) were included. Selenium supplementation in comparison to placebo was associated with lower mortality (odds ratio, 0.73; 95% CI, 0.54, 0.98; p = 0.03; I2 = 0%). Among patients receiving and not receiving selenium, there was no difference in ICU length of stay (mean difference, 2.03; 95% CI, -0.51, 4.56; p = 0.12; I2 = 0%) or nosocomial pneumonia (odds ratio, 0.83; 95% CI, 0.28, 2.49; p = 0.74; I2 = 56%).

Abstract: Alhazzani. The Effect of Selenium Therapy on Mortality in Patients With Sepsis Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Crit Care Med 2013; epublished April 12th


Australian Critical Care:     Subglottic Suctioning

In a systematic review and meta analysis, consisting of 9 randomized trials, subglottic drainage was estimated to reduced the risk of ventilator-associated pneumonia (fixed-effect relative risk0.52, 95% CI, 0.42–0.65), but not of  ICU mortality (RR 1.05 (95% CI, 0.86–1.28) or for hospital mortality was 0.96 (95% CI, 0.81–1.12). Subglottic drainage was associated with a reduced duration of mechanical ventilation was −1.04 days (95% CI, −2.79–0.71).

Abstract:  Frost. Subglottic secretion drainage for preventing ventilator associated pneumonia: A meta-analysis. Aust Crit Care 2013; epublished April 11th


International Journal of Antimicrobial Agents:     MRSA Therapy

An and colleagues undertook a meta analysis (9 RCTs, n=5249) to compare the efficacy and safety of linezolid with vancomycin for meticillin-resistant Staphylococcus aureus (MRSA)-related infections. Linezolid was associated with superior efficacy compared with vancomycin for MRSA-related infection in terms of clinical treatment success [8 RCTs, 2174 patients, odds ratio =1.77, 95% CI 1.22–2.56] and microbiological treatment success (9 RCTs, 1555 patients, OR=1.78, 95% CI 1.22–2.58). Although no difference was found regarding the overall incidence of drug-related adverse events and serious AEs between the linezolid and vancomycin therapy groups (drug-related AEs, 8 RCTs, 5034 patients, OR=1.20, 95% CI 0.98–1.48; SAEs, 5 RCTs, 2072 patients, OR=1.00, 95% CI 0.74–1.36), the linezolid therapy group was associated with significantly fewer patients experiencing abnormal renal function (4 RCTs, 2531 patients, OR=0.39, 95% CI 0.28–0.55).

Abstract:  An. Linezolid versus vancomycin for meticillin-resistant Staphylococcus aureus infection: a meta-analysis of randomised controlled trials. International Journal of Antimicrobial Agents 2013;41(5):426-433


Infection Control and Hospital Epidemiology:     ICU-Acquired Infections

Salgado and colleagues undertook a randomized control trial in 614 patients placed randomly in available rooms with or without copper alloy surfaces, to determine the effect of copper surfaces  on rates of hospital-acquired infections and/or colonization with methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Enterococcus (VRE).  HAIs and MRSA or VRE colonization rates were significantly lower in patients treated in rooms with copper surfaces than standard rooms (0.071 versus 0.123, p=0.020). For HAI only, the rate was reduced from 0.081 to 0.034 (p=0.013). 

Full Text:  Salgado. Copper Surfaces Reduce the Rate of Healthcare-Acquired Infections in the Intensive Care Unit. Infection Control and Hospital Epidemiology 2013;34(5):479-486


Mayo Clinic Proceedings:     L-Carnitine in Acute Myocardial Infarction

DiNicolantonio and colleagues completed a systematic review and meta-analysis (13 controlled trials, n=3629) to evaluate the effects of L-carnitine in the setting of acute myocardial infarction.
This intervention was associated with reductions in all-cause mortality (odds ratio 0.73; 95% CI 0.54-0.99; p=0.05; risk ratio 0.78; 95% CI 0.60-1.00; p=.005), incidence of ventricular arrthymias (RR 0.35; 95% CI 0.21-0.58; P<.0001), and development of angina (RR 0.60; 95% CI 0.50-0.72; p<.00001), with no reduction in the development of heart failure (RR 0.85; 95% CI 0.67-1.09; p=0.21) or myocardial reinfarction (RR 0.78; 95% CI 0.41-1.48; p=0.45).

Full Text:  DiNicolantonio. L-carnitine in the secondary prevention of cardiovascular disease: Systematic review and meta-analysis. Mayo Clin Proc 2013;epublished April 12th



Critical Care:     European Haemorrhage Guideline


Journal of the American College of Cardiology:     Type B Aortic Dissection


Nephrology:     Initiating Renal Replacement Therapy at End of Life


Annals of Internal Medicine:     Social Medicine



New England Journal of Medicine:     Mechanical Ventilation


Journal of the American Medican Association:     Bacterial Resistance


Nature:     H7N9 Influenza


Critical Care:     High-Frequency Oscillation


Review - Clinical


Brazilian Journal of Intensive Care:     Septic Encephalopathy Biomarkers



Journal of Clinical Pharmacology:     Levosimendan


Clinical and Experimental Pharmacology and Physiology:     Ticagrelor


Clinical Pharmacology: Advances and Applications:     Ticagrelor


Swiss Medical Weekly:     Cardiac Arrest


Vascular Health and Risk Management:     Takosubo Cardiomyopathy


Annals of Cardiothoracic Surgery:     Type A Aortic Dissection



Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine:     Inhalational Injury


Columbian Journal of Anaesthesiology:     Rapid Sequence Intubation


Current Opinion in Anesthesiology:     Thoracic Ultrasound


Respiratory Research:     Pulmonary Fibrosis


Respirology:     Lung Stem Cells



Clinical Gastroenterology and Hepatology:     Small Bowel Tissue Engineering



Brazilian Journal of Intensive Care:     Protein Requirements in the Critically Ill



Liver International:     Liver Tissue Engineering



Clinical and Experimental Pharmacology and Physiology:     Renal Oxygenation



Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine:     Thromboelastography


Current Opinion in Anesthesiology:     Coagulation Management in Cardiac Surgery


Columbian Journal of Anaesthesiology:     Perioperative Paediatric Bleeding



ISRN Cardiology:     Troponin Measurement in Sepsis


Journal of Infectious Diseases:     Malaria


Journal of Emergency Trauma and Shock:     Sternal Fracture


Journal of Emergency Trauma and Shock:     Combined Tracheoesophageal Trauma



Journal of Thoracic Diseases:     Critical Care Update

Critical Care Nurse:     Dogmatic Practice


Journal of Pharmacology and Pharmacotherapeutics:      Drug Reactions in the Elderly


Review - Non-Clinical

BMC Biology:     Open Access Publications


Journal of Pharmacology and Pharmacotherapeutics:      Writing and Publishing


Journal of Pharmacology and Pharmacotherapeutics:     Computer-Assisted Undergraduate Learning



I hope you find these brief summaries and links useful.

Until next week



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