Newsletter 92 / September 8th 2013




Welcome to the 92nd 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 week's research studies include interventional investigations evaluating thrombomodulin in sepsis, rifamixin in hepatic encephalopathy, venous access, and cardiac resynchronization. Meta analyses examine benzodiazepine sedation, heparin venothromboembolism prophylaxis, renal biomarkers, contrast-induced acute kidney injury and risks with NSAIDs. Observational studies focus on PCI post cardiac arrest, door-to-balloon time in PCI, pharmacotherapy in heart failure, neuromuscular blockade during mechanical ventilation, cardioverter-defibrillators, bioreactance cardiac output monitors, and asthma outcome prediction.

This week's guidelines address acute pancreatitis and traumatic vascular injuries. There are commentaries on the recent HOPE-ICU study, REDOXs study, 3D organ printing and peer review.

Amongst the clinical review articles are papers on diastolic heart failure, aortic syndromes, ventricular assist devices, mechanical ventilation for neurosurgical patients, fluid management in the setting of acute kidney injury, therapeutic hypothermia, anaemia and septic shock. The latest articles recently made open access from the major journals are included, although there are surprisingly few.

The topic for This Week's Papers is ischaemic stroke, starting with a paper on arterial recanalization in tomorrow's Paper of the Day.

In case you've missed it, the next Critical Care Reviews Meeting will be held on Friday January 24th outside Belfast.



Randomized Controlled Trials

Critical Care Medicine:     Thrombomodulin in Sepsis

Vincent and colleagues completed an international multicenter, blinded, randomized, placebo-controlled phase II trial in patients with sepsis and suspected disseminated intravascular coagulation, examining recombinant thrombomodulin (ART-123; 0.06 mg/kg/d, n=371) for 6 days or placebo (n=370) and reported:

  1. Twenty-eight-day mortality of 17.8% in the ART-123 group and 21.6% in the placebo group, with a confusing statistical analysis: "Cochran–Mantel–Haenszel two-sided p value of 0.273 in favor of ART-123, which met the predefined statistical test for evidence suggestive of efficacy" .
  2. Recombinant thrombomodulin was associated with
    • reduced concentrations of d-dimer, prothrombin fragment F1.2 and TATc.
    • no effect on days event-free and alive, organ function, inflammatory markers, bleeding or thrombotic events or new infections.
  3. In post hoc analyses, greatest benefit from recombinant thrombomodulin was seen in patients with at least one organ system dysfunction and an international normalized ratio greater than 1.4 at baseline.

Abstract:  Vincent. A Randomized, Double-Blind, Placebo-Controlled, Phase 2b Study to Evaluate the Safety and Efficacy of Recombinant Human Soluble Thrombomodulin, ART-123, in Patients With Sepsis and Suspected Disseminated Intravascular Coagulation. Crit Care Med 2013;41(9):2069-2079


American Journal of Gastroenterology:      Hepatic Encephalopathy

Sharma and colleagues performed a double-blind randomized controlled trial in 120 patients with hepatic encephalopathy, with a mean Child–Turcotte–Pugh score of 9.7±2.8 and model MELD score of 24.6±4.2, comparing lactulose plus rifaximin 1,200mg/day (n=63) with lactulose plus placebo (n=57), and found

  1. rfamixin therapy was associated with
    • increased reversal of encephalopathy (76% versus 50.8%; P<0.004)
    • decreased mortality (23.8% vs. 49.1%, P<0.05)
    • less deaths from sepsis (7 versus 17; P=0.01)
    • shorter hospital stay (5.8±3.4 vs. 8.2±4.6 days; P=0.001)
  2. there were no differences in
    • gastrointestinal bleed (4 versus 4) 
    • hepatorenal syndrome (4 versus 7)

Abstract:  Sharma. A Randomized, Double-Blind, Controlled Trial Comparing Rifaximin Plus Lactulose With Lactulose Alone in Treatment of Overt Hepatic Encephalopathy. Am J Gastroenterol 2013;108:1458-1463


Critical Care Medicine:     Venous Access

Ricard and colleagues undertook a multicenter, parallel-group, randomized, controlled, open-label trial comparing catheter-related complications between central (n=135) and peripheral (n=128) venous catheters., and found

  1. more major catheter-related complications with peripheral devices (133 vs 87; p=0.02)
  2. more minor catheter-related complications with central devices (248 versus 201; p=0.06)
  3. Kaplan–Meier estimates of survival probability did not differ between the two groups

Abstract: Ricard. Central or Peripheral Catheters for Initial Venous Access of ICU Patients: A Randomized Controlled Trial. Crit Care Med 2013;41(9):2108-2115


Circulation:     Beta Blockade in Myocardial Infarction

Ibanez and colleagues completed a randomized controlled trial in 270 patients with Killip-class ≤II anterior ST-segment elevation myocardial infarction undergoing PCI within 6 hours of symptoms onset, comparing IV metoprolol (n=131) with no metoprolol (n=139), and found:

  1. early IV metoprolol was associated with
    • reduced infarct size as assessed with MRI (25.6±15.3 versus 32.0±22.2 grams; adjusted difference -6.52; 95% CI -11.39 to -1.78; P=0.012)
    • reduced infarct size in patients with pre-PCI TIMI flow grade 0/1 (adjusted treatment difference -8.02; 95% CI -13.01 to -3.02; P=0.0029)
    • reduced creatinine kinase level
    • higher left ventricular ejection fraction (adjusted difference 2.67%; 95% CI 0.09% to 5.21%; P=0.045)
  2. There was no difference in the composite endpoint of death, malignant ventricular arrhythmia, cardiogenic shock, atrioventricular block and reinfarction at 24 hours (metoprolol 7.1% versus 12.3%; p=0.21)

Abstract:  Ibanez. Effect of Early Metoprolol on Infarct Size in ST-Segment Elevation Myocardial Infarction Patients Undergoing Primary PCI: The METOCARD-CNIC Trial. Circulation 2013;epublished September 3rd


New England Journal of Medicine:     Cardiac-Resynchronization Therapy

Ruschitzka et al performed a randomized trial in 809 patients with New York Heart Association class III or IV heart failure, a left ventricular ejection fraction of 35% or less, a QRS duration of less than 130 msec, and echocardiographic evidence of left ventricular dyssynchrony, comparing cardiac-resynchronization therapy capability turned on or off, and found:

  1. cardiac-resynchronization therapy was associated with
    • no effect on the composite endpoint of death from any cause or first hospitalization for worsening heart failure (CRT 28.7% vs. 25.2%; hazard ratio 1.20; 95% CI 0.92 to 1.57; P=0.15)
    • increased mortality (CRT 11.1% versus 6.4%; HR 1.81; 95% CI 1.11 to 2.93; P=0.02)

Full Text:  Ruschitzka. Cardiac-Resynchronization Therapy in Heart Failure with a Narrow QRS Complex (EchoCRT study). New Engl J Med 2013;epublished September 3rd


Meta Analysis

Critical Care Medicine:     Benzodiazepine Sedation

Fraser et al reviewed six randomized trials (n=1,235) comparing benzodiazepine sedation with nonbenzodiazepine sedation in mechanically ventilated adult patients, and found

  1. nonbenzodiazepine sedation was associated with reduced
    • ICU length of stay (6 studies; difference 1.62 days; 95% CI 0.68–2.55; I2 = 0%; p = 0.0007)
    • duration of mechanical ventilation (4 studies; difference 1.9 days; 95% CI 1.70–2.09; I2 = 0%; p < 0.00001)
  2. there was no difference between sedation strategies with regard to
    • prevalence of delirium (2 studies; risk ratio 0.83; 95% CI 0.61–1.11; I2 = 84%; p = 0.19)
    • short-term mortality rate (4 studies; risk ratio 0.98; 95% CI, 0.76–1.27; I2 = 30%; p = 0.88)

Abstract:  Fraser. Benzodiazepine Versus Nonbenzodiazepine-Based Sedation for Mechanically Ventilated, Critically Ill Adults: A Systematic Review and Meta-Analysis of Randomized Trials. Critical Care Med 2013;41(9):S30-S38


New England Journal of Medicine:     Renal Biomarkers

Shilpaket et al performed a meta-analysis of 11 general-population studies (n=90,750 participants) and 5 studies of cohorts with chronic kidney disease (n=2,960 participants) comparing cystatin C with creatinine for determining mortality risk based on kidney function, and found:

  1. when eGFR was measured based on cystatin C, rather than creatinine, there was a higher incidence of reduced eGFR (<60ml/min/1.73 m2) (13.7% versus 9.7%)
  2. reclassifying eGFR to a higher value with the measurement of cystatin C, as compared with creatinine, was associated with a reduced risk of all three study outcomes: risks of death, death from cardiovascular causes, and death from end-stage renal disease
  3. reclassifying eGFR to a lower value with the measurement of cystatin C, as compared with creatinine, was associated with an incerased risk of all three study outcomes
  4. a net reclassification improvement with the measurement of cystatin C, as compared with creatinine, of:
    • 0.23 (95% CI 0.18 to 0.28) for death 
    • 0.10 (95% CI 0.00 to 0.21) for end-stage renal disease

Abstract:  Shlipak. Cystatin C versus Creatinine in Determining Risk Based on Kidney Function. N Engl J Med 2013;369:932-943  


Journal of the American College of Cardiology:     Contrast-Induced Acute Kidney Injury

Sadat and colleagues pooled data from nine randomized controlled trials (n=1,536) evaluating the effect of ascorbic acid, versus placebo or active control, on the development of contrast-induced acute kidney injury, and found ascorbic acid was associated with:

  1. a reduced risk for the development of CI-AKI (risk ratio 0.672, 95% CI 0.466-0.969; p=0.034)

Abstract:  Sadat. Does ascorbic acid protect against contrast-induced acute kidney injury in patients undergoing coronary angiography - a systematic review with meta-analysis of randomized controlled trials. J Am Coll Cardiol 2013;epublished August 15th


Critical Care Medicine:     Heparin Prophylaxis

Alhazzani and colleagues reviewed seven randomized studies (n=7,226) comparing any heparin (unfractionated heparin or low-molecular-weight heparin) with each other or no anticoagulant prophylaxis, and found:

  1. any heparin thromboprophylaxis, compared with placebo, was associated with
    • reduced rates of deep vein thrombosis (pooled risk ratio 0.51; 95% CI 0.41 - 0.63; p < 0.0001; I2 = 77%) and pulmonary embolism (risk ratio 0.52; 95% CI 0.28 - 0.97; p = 0.04; I2 = 0%)
    • no effect on rates of symptomatic deep vein thrombosis (risk ratio 0.86; 95% CI 0.59 - 1.25; p = 0.43), major bleeding (risk ratio 0.82; 95% CI 0.56 - 1.21; p = 0.32; I2 = 50%) or rates of mortality (risk ratio 0.89; 95% CI 0.78 - 1.02; p = 0.09; I2 = 0%) 
  2. unfractionated heparin, compared with low-molecular-weight heparin, was associated with
    • reduced rates of pulmonary embolism (risk ratio 0.62; 95% CI 0.39 - 1.00; p = 0.05; I2 = 53%)
    • reduced rates of symptomatic pulmonary embolism (risk ratio 0.58; 95% CI 0.34 - 0.97; p = 0.04)
    • no effect on rates of deep vein thrombosis (risk ratio 0.90; 95% CI 0.74 - 1.08; p = 0.26; I2 = 0%), symptomatic deep vein thrombosis (risk ratio 0.87; 95% CI 0.60 - 1.25; p = 0.44; I2 = 0%), major bleeding (risk ratio 0.97; 95% CI, 0.75 - 1.26; p = 0.83; I2 = 0%), or mortality (risk ratio 0.93; 95% CI 0.82 - 1.04; p = 0.20; I2 = 31%)

Abstract:  Alhazzani. Heparin Thromboprophylaxis in Medical-Surgical Critically Ill Patients: A Systematic Review and Meta-Analysis of Randomized Trials. Crit Care Med 2013;41(9):2088-2098


Lancet:     NSAIDS

In a large meta-analyses of 280 trials of NSAIDs versus placebo (n=124 513, 68 342 person-years) and 474 trials of one NSAID versus another NSAID (229 296 participants, 165 456 person-years), it was found that:

  1. coxibs (rate ratio 1·37, 95% CI 1·14—1·66; p=0·0009) and diclofenac (RR 1·41, 1·12—1·78; p=0·0036) increased major vascular events, largely due to coronary events (coxibs 1·76, 1·31—2·37; p=0·0001; diclofenac 1·70, 1·19—2·41; p=0·0032)
  2. ibuprofen increased major coronary events (2·22, 1·10—4·48; p=0·0253), but not major vascular events (1·44, 0·89—2·33)
  3. naproxen did not significantly increase major vascular events (0·93, 0·69—1·27)
  4. vascular death was increased significantly by coxibs (1·58, 99% CI 1·00—2·49; p=0·0103) and diclofenac (1·65, 0·95—2·85, p=0·0187), non-significantly by ibuprofen (1·90, 0·56—6·41; p=0·17), but not by naproxen (1·08, 0·48—2·47, p=0·80)
  5. for every 1000 patients receiving a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal, relative to placebo
  6. the proportional effects on major vascular events were independent of baseline characteristics, including vascular risk
  7. heart failure risk was roughly doubled by all NSAIDs
  8. all NSAID regimens increased upper gastrointestinal complications (coxibs 1·81, 1·17—2·81, p=0·0070; diclofenac 1·89, 1·16—3·09, p=0·0106; ibuprofen 3·97, 2·22—7·10, p<0·0001; and naproxen 4·22, 2·71—6·56, p<0·0001)

Abstract:  Coxib and traditional NSAID Trialists' Collaboration. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013;382(9894):769-779   


Journal of Thoracic Diseases:     Chlorhexidine Bathing

Chen et al reviewed data from 12 studies investigating whether daily bathing with chlorhexidine gluconate reduces rates of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE), and found:

  1. daily application of chlorhexidine significantly lowered the acquired colonization of MRSA (incidence rate ratio 0.58, 95% CI 0.41-0.82) and VRE (incidence rate ratio 0.51, 95% CI 0.36-0.73)
  2. chlorhexidine bathing would significantly reduce MRSA infection (IRR 0.56, 95% CI 0.37-0.85), MRSA ventilator associated pneumonia (IRR 0.22, 95% CI 0.07-0.64) and VRE infection (IRR 0.57, 95% CI 0.33-0.97)
  3. no significant publication bias was found in this meta-analysis

Abstract:  Chen. Effects of daily bathing with chlorhexidine and acquired infection of methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus: a meta-analysis. J Thorac Dis 2013;5(4):518-524


Observational Studies

Resuscitation:     Cardiac Arrest

Hollenbeck and colleagues completed a retrospective observational study using data from a prospective cohort of 754 consecutive comatose patients treated with therapeutic hypothermia following cardiac arrest, and found:

  1. in the cohort of 269 patients (35.7%) who had a cardiac arrest due to a ventricular arrhythmia without STEMI and were treated with therapeutic hypothermia
    • 122 (45.4%) received cardiac catheterization while comatose (early cardiac catheterization)
    • there was no difference in rates of acute coronary occlusion between patients treated with early cardiac catheterization (26.6%) compared with patients treated with late cardiac catheterization (29.3%; p=0.381)
    • patients treated with early cardiac catheterization were more likely to survive to hospital discharge compared to those not treated with cardiac catheterization (65.6% versus 48.6%; p=0.017)
  2. in a multivariate regression model, early cardiac catheterization was independently associated with a significant reduction in the risk of death (OR 0.35, 95% CI 0.18–0.70, p=0.003)

Abstract:  Hollenbeck. Early cardiac catheterization is associated with improved survival in comatose survivors of cardiac arrest without STEMI. Resuscitation 2013;epublished August 7th


New England Journal of Medicine:     PCI

In an observational study using data from the American CathPCI Registry, Menees and colleagues examined whether improving PCI door-to-balloon times in 96,783 patients undergoing primary PCI for ST-segment elevation myocardial infarction have been accompanied by a decline in mortality, and found:

  1. improvements in door-to-balloon times over time
    • median door-to-balloon times declined significantly from 2005/6 to 2008/9  (83 minutes versus 67 minutes; P<0.001)
    • more patients achieved a door-to-balloon time of 90 minutes or less from 2005/6 to 2008/9 (59.7% versus 83.1%; P<0.001)
  2. no improvement in mortality
    • unadjusted in-hospital mortality (2005/6 to 2008/9:  4.8% versus 4.7%, P=0.43 for trend)
    • risk-adjusted in-hospital mortality (2005/6 to 2008/9: 5.0% versus 4.7%, P=0.34)
    • unadjusted 30-day mortality (P=0.64)

Abstract:  Menees. Door-to-Balloon Time and Mortality among Patients Undergoing Primary PCI. N Engl J Med 2013;369:901-909  


Critical Care Medicine:     Cardiogenic Shock

Van Diepen and colleagues performed a secondary analysis of the TRIUMPH randomized controlled trial, examining the effects of beta blocker and/or renin-angiotensin-aldosterone system blocker therapy in patients with ongoing cardiogenic shock, and found

  1. 66 patients (27.5%) had either beta blocker or renin-angiotensin-aldosterone system blocker therapy administered within the first 24 hours after the diagnosis of cardiogenic shock
  2. 30-day mortality among patients was higher in patients who received beta or renin-angiotensin-aldosterone system blockers prior to cardiogenic shock resolution (27.3% vs 16.9%; adjusted hazard ratio 2.36; 95% CI 1.06-5.23; p = 0.035).
  3. Compared with patients not given beta or renin-angiotensin-aldosterone system blockers, the 30-day mortality was
    • higher among patients treated only with beta blockers (33.3% vs 16.9%, p = 0.017)
    • not different between those only treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (18.2% vs 16.9%, p = 1.000)

Abstract: van Diepen. Incidence and Outcomes Associated With Early Heart Failure Pharmacotherapy in Patients With Ongoing Cardiogenic Shock. Crit Care Med 2013;epublished August 26th


Critical Care Medicine:     Neuromuscular Blockers

In an database observational study including 7,864 patients with sepsis and a respiratory infection requiring mechanical ventilation, including 1,818 (23%) who were treated with a neuromuscular blocking agent by hospital day 2, Steingrub et al found:

  1. Patients who received neuromuscular blocking agents were
    • younger (mean age, 62 vs 68),
    • more likely to be treated with vasopressors (69% vs 65%)
    • had a lower in-hospital mortality rate (31.9% vs 38.3%, p < 0.001)
  2. using propensity analysis, in 3,518 patients, neuromuscular blockade was associated with a reduced risk of in-hospital mortality (risk ratio 0.88; 95% CI 0.80 - 0.96)

Abstract:  Steingrub. Treatment With Neuromuscular Blocking Agents and the Risk of In-Hospital Mortality Among Mechanically Ventilated Patients With Severe Sepsis. Crit Care Med 2013;epublished August 26th


Other observational studies of interest

American Journal of Respiratory and Critical Care Medicine:      ICU Strain   

Abstract: Gabler. Mortality among Patients Admitted to Strained Intensive Care Units. Am J Respir Crit Care Med 2013;epublished August 30th


Circulation:    Implantable-Cardioverter Defibrillator

Full Text:  Weiss. Safety and Efficacy of a Totally Subcutaneous Implantable-Cardioverter Defibrillator. Circulation 2013;128:944-953


British Journal of Anaesthesia:     Bioreactance Cardiac Output Monitoring

Abstract:  Kupersztych-Hagege. Bioreactance is not reliable for estimating cardiac output and the effects of passive leg raising in critically ill patients. Br J Anaesth 2013;epublished August 28th


Emergency Medical Journal:     Asthma

Abstract:  Goodacre. Prediction of unsuccessful treatment in patients with severe acute asthma. Emerg Med J 2013;epublished August 29th  


Position Statement

American Journal of Gastroenterology:     Acute Pancreatitis


Journal of Trauma and Acute Care Surgery:     Traumatic Vascular Injury


The Lancet Respiratory Medicine:     HOPE-ICU Delirium Study


Journal of Parenteral and Enteral Nutrition:     REDOXs Study


The Scientist:     3D Printing


Springer Science Reviews:     Peer Review 

Review - Clinical


Cleveland Clinic Journal of Medicine:     Transient Ischaemic Attack



Journal of Clinical Medical Research:     Diastolic Heart Failure

Biomarker Insights:     Cardiac Biomarkers


Cleveland Clinic Journal of Medicine:     Chest Pain


Circulation:     Acute Aortic Syndrome

Antioxidants & Redox Signaling:     Atrial Fibrillation


Therapeutic Advances in Chronic Disease:     Aliskiren


European Respiratory Review:     Pulmonary Fibrosis



Nephron Clinical Practice:     Fluid Balance



Inflammation & Allergy - Drug Targets:     Vitamin D



F1000 Prime Reports:     Therapeutic Hypothermia



Journal of Blood Transfusion:     Anaemia and Blood Transfusion



Clinical Science:     Septic Shock


Cleveland Clinic Journal of Medicine:     Azithromycin



Pathobiology:     Immunosuppression



Journal of Blood Transfusion:     Stem Cell Research


Recently Made Open Access Articles from Major Journals


American Journal of Respiratory and Critical Care Medicine

Critical Care


Anesthesia & Analgesia


British Journal of Anaesthesia



Critical Care





I hope you find these brief summaries and links useful.

Until next week