Newsletter 138 / July 27th 2014



Welcome to the 138th 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, guidelines, commentaries and editorials from hundreds of clinical and scientific journals.

In news the BMJ have completed a remarkable investigation in the research supporting the monitoring-free use of dabigatran. This week's research studies include randomized controlled trials on vasodilating the microcirculation, and tedizolid for skin and skin-structure infections; an interventional study on hydrocortisone therapy for brain dead potential organ donors; meta analyses on albumin for sepsis, fluid resuscitation in sepsis, fibrinogen therapy for bleeding, and noninvasive haemoglobin concentration measurement; plus observational studies  on early sedation strategies, and extracorporeal cardiac life support. Additional studies investigate brain microdialysis, arginine in septic shock, distinguishing SIRS from sepsis, and ventilator-associated pneumonia.

This week's guidelines address intraoperative neurophysiological monitoring, endoscopy for variceal haemorrhage, and social media for physicians. The latest edition of JICS provides four study critiques, looking at the STATIN-VAP study, SEPSISPAM study, IMPROVE study, and the Morelli paper on β blockade in sepsis. Editorials review pre-operative echo, predicting fluid responsiveness and supporting children with relatives in the ICU; clinical commentaries focus on starches and fast-track anaesthesia, while non-clinical commentaries include two more papers from the fantastic statistics and research methodology series by Philip Sedgwick, published in the BMJ.  There are case reports on permissive hypotension in traumatic brain injury and management of the bleeding Jehovah's Witness patient. There is also correspondence in the New England Journal of Medicine on the ProCESS study.

Amongst the clinical review article are papers on cerebral perfusion pressure in traumatic brain injury, anaesthesia-related seizures, volume therapy, permissive hypercapnoea, perioperative positive pressure ventilation, oxygen therapy, mesenteric ischaemia, pregnancy-related liver disorders, acute kidney injury, nephrotoxicity, diabetic ketoacidosis, haemorrhage management in patients receiving the new oral anticoagulants, intravenous iron, paracetamol overdose, pharmacokinetics in the critically ill and humanitarian catastrophies. Continuing our focus on excellent open access critical care journals, the Topic of the Week is a selection of papers from the Indian Journal of Critical Care Medicine, starting with a paper on the use of video laryngoscopes in the ICU, in tomorrow's Paper of the Day.

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Upcoming Meetings

Critical Care Reviews Meeting 2015

The 2015 Critical Care Reviews Meeting, being held in association with the Northern Ireland Intensive Care Society, will be held on Friday January 23rd, at the Galgorm Resort and Spa, outside Belfast, Northern Ireland. Further details will follow over the next couple of months, with registration opening the first week in October. The impressive list of speakers includes Clifford Deutschman (USA), the immediate past president of the Society of Critical Care Medicine, Niklas Nielsen (Sweden), Eddy Fan (Canada), Kathy Rowan (England), Danny McAuley, Eamon McCoy, and John Hinds (Northern Ireland), plus a host of local intensivists. The theme of the meeting is to discuss the biggest research findings of the past year, with the aim of deciding whether you should implement these results into your current practice.

SMACC Chicago

The next SMACC conference will be held June 23rd to 26th, in Chicago, USA. Just like the Critical Care Reviews Meeting, this is a not-for-profit event, run by a team interested in sharing knowledge in a fun, modern way. It's a conference like no other. Further details will be out soon on the SMACC website.

Intensive Care Society State-of-the-Art Meeting

The 2014 ICS State-of-the-Art Meeting is on December 8th to 10th at the Excel Arena in London. The speakers have just been announced, with further details available from the ICS website.

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Critical Care Horizons

Critical Care Horizons is a fresh new voice in the critical care literature, offering thought-provoking, cutting-edge commentary and opinion papers, plus state-of-the-art review articles. The journal is free to publish with and free to read, opening authorship opportunity to all. The energetic editorial board consists of a deliberate mix of clinicians active in social media and world renowned academics, all driven by a desire to improve the care we offer our patients, and operate without financial gain or incentive. A call for papers has been issued, so if you have something interesting to say, and can say it in an engaging manner, please get in touch. The first issue will be released on January 1st 2015.

COI - I am the editor-in-chief of this new journal, but work in a voluntary capacity, as do all the editors.

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Dabigatran Controversy

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Randomized Controlled Trials

van der Voort and colleagues completed a single-centre, randomised controlled pilot study in 90 patients (65 analyzed) with severe sepsis and septic shock, comparing a resuscitation strategy targeting early opening of the constricted microcirculation with active vasodilatation (using nitroglycerin, enoximone, dopamine and dexamethasone to achieve a microvascular flow index, measured by sublingual side-stream dark field imaging, more than 2.5.) with a standard resuscitation group (using fluids, noradrenaline, dobutamine and hydrocortisone to achieve a mean arterial pressure > 60 mmHg, cardiac index > 2.5 l/min/m2 and ScvO2 > 70%) and found:

  1. microcirculation resuscitation was associated with
    • a mean duration of 7.0 (4.6) hours therapy to achieve this
    • greater administration of fluids
    • similar administration of noradrenaline to the control group
  2. per protocol analysis
    • no statistical difference in SOFA score decrease at day 4 (P = 0.64) (1° outcome)
    • both groups had a statistically significant reduction in SOFA score at day 4 compared with admission
      • microcirculation resuscitation 1.2; P = 0.028
      • standard resuscitation groups 1.6; P = 0.045

Abstract:  van der Voort. Testing a conceptual model on early opening of the microcirculation in severe sepsis and septic shock: A randomised, controlled pilot study. European Journal of Anaesthesiology 2014;epublished July 16th 

Moran and colleagues undertook an international multi-centre, randomised, double-blind, phase 3, non-inferiority trial, comparing tedizolid (200mg IV once daily for 6 days, n=332) with linezolid (600mg IV twice daily for 10 days, n=334), with an endpoint of early clinical response (≥20% reduction in lesion area at 48—72 h compared with baseline), with a non-inferiority margin of −10%, and using an intention to treat analysis, found:

  1. tedizolid was non-inferior to linezolid
    • early clinical response
      • tedizolid group 85% vs linezolid group 83%
      • difference 2·6%, 95% CI −3·0 to 8·2
  2. tedizolid was associated with less gastrointestinal adverse effects
    • 16% vs 20%
  3. discontinuation of study drug due to treatment-emergent adverse events occurred in
    • tedizolid group n=1 (<1%) vs linezolid n=4 (1%)

Abstract:  Moran. Tedizolid for 6 days versus linezolid for 10 days for acute bacterial skin and skin-structure infections (ESTABLISH-2): a randomised, double-blind, phase 3, non-inferiority trial (ESTABLISH-2). Lancet Infectious Diseases 2014;14(8):696-705

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Pinsard and colleagues performed a prospective, multicenter, cluster study, comparing the effect of low-dose steroid administration (n=102) with standard care only (n=157) on noradrenaline dosing in 259 brain dead potential organ donors, and found:

  1. low-dose hydrocortisone administration was associated with 
    • lower mean dose of noradrenaline administered after brain death
      • 1.18 ± -0.92 mg/H vs. 1.49 ± -1.29 mg/H: P = 0.03
    • shorter duration of vasopressor support
      • 874 min vs. 1160 min: P < 0.0001
    • more frequent weaning of noradrenaline prior to aortic clamping
      • 33.8% vs. 9.5%: P < 0.0001
    • although more patients in the steroid group received norepinephrine before brain death
      • 80% vs. 66%: P = 0.03
    • an increased probability of weaning norepinephrine
      • HR 4.67, 95% CI 2.30 to 9.49; p<0.0001
  2. no observed benefits of the steroid administration on primary function recovery of transplanted grafts

Full Text:  Pinsard. Interest of low-dose hydrocortisone therapy during brain-dead organ donor resuscitation: the CORTICOME study. Critical Care 2014;18:R158

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Meta Analyses

Patel et al reviewed data from 16 randomized controlled trials evaluating the use of pooled human albumin solutions for fluid volume expansion and resuscitation in 4,190 critically ill septic adults, and found:

  1. basic data (medians)
    • 70.0 g daily of pooled human albumin was administered over 3 days
    • patient age 60.8 years
  2. albumin administration was associated with
    • no statistical reduction in
      • relative risk of death
        • albumin group vs control fluid group (RR 0.94; 95% CI 0.87 to 1.01; P=0.11; I2=0%)
          • trial sequential analysis corrected for random error (95% CI 0.85 to 1.02; D2=0%)
          • 88% of the required information size (meta-analysis sample size) of 4,894 patients was achieved
          • the cumulative effect size measure (z score) entered the futility area, supporting the notion of no relative benefit of albumin
            • GRADE quality of evidence moderate
        • albumin vs crystalloid fluid (n=3,878)
          • relative risk 0.93; 95% CI 0.86 to 1.01; P=0.07; I2=0%
            • GRADE quality of evidence was high; 79.9% of required information size
        • albumin vs colloid fluids (n=299)
          • relative risk 1.04; 0.79 to 1.38; P=0.76; I2=0%
            • GRADE quality of evidence very low; 5.8% of required information size
  3. excluding studies at high risk of bias in a predefined subgroup analysis
    • the finding of no mortality benefit remained
    • the cumulative z score was outside the boundary of futility
  4. the meta-analysis was robust to sensitivity, subgroup, meta-regression, and trial sequential analyses

Full Text:  Patel. Randomised trials of human albumin for adults with sepsis: systematic review and meta-analysis with trial sequential analysis of all-cause mortality. BMJ 2014;349:g4561

Rochwerg et al pooled data from 14 randomized controlled trials, evaluating the effect of different resuscitative fluids on mortality in 18,916 patients with sepsis, and found:

  1. network meta-analysis at the 4-node level showed
    • higher mortality with
      • starches than with crystalloids (high confidence)
    • lower mortality with
      • albumin vs crystalloids (moderate confidence)
      • albumin vs starches (moderate confidence)
  2. network meta-analysis at the 6-node level showed
    • lower mortality with
      • albumin vs saline (moderate confidence) 
      • albumin vs low-molecular-weight starch (low confidence)
      • balanced crystalloids vs saline (low confidence) 
      • balanced crystalloids v low- and high-molecular-weight starches (moderate confidence)
  3. the meta analysis was limited by
    • case mix herterogeneity
    • fluids evaluated
    • duration of fluid exposure
    • risk of bias
    • low confidence in most estimates of effect due to imprecise estimates for several comparisons

Abstract:  Rochwerg. Fluid Resuscitation in Sepsis: A Systematic Review and Network Meta-analysis. Ann Intern Med 2014;epublished July 22nd

Lund et al reviewed data from 7 randomized controlled trials and 23 non-randomized trials, evaluating the use of fibrinogen concentrate in bleeding patients, and found:

  1. of the 7 randomized controlled trials (n=268)
    • these studies were at high risk of bias 
    • none reported a significant effect on mortality
    • 2 RCTs found a significant reduction in bleeding 
    • 5 RCTs found a significant reduction in transfusion requirements
    • all had substantial shortcomings
  2. of the 23 non-randomised studies (n=2,825)
    • 11/23 studies included a control group
    • 3/11 found a reduction in transfusion requirements
    • mortality was reduced in two
    • bleeding was reduced in one

Abstract:  Lund. Fibrinogen concentrate for bleeding – a systematic review. Acta Anaesthesiologica Scandinavica 2014;epublished July 24th

Sang-Hyun and colleagues reviewed 32 studies (n=4,425) examining the accuracy and precision of noninvasive hemoglobin monitoring devices, as compared with central laboratory hemoglobin measurements, and found:

  1. an overall pooled random-effects (mean difference/SD; noninvasive—central laboratory): 
    • 0.10 ± 1.37 g/dL (-2.59 to 2.80 g/dL, I2 = 95.9% for mean difference and 95.0% for SD)
  2. in subgroup analysis
    • 13 perioperative studies:
      • 0.39 ± 1.32 g/dL (-2.21 to 2.98 g/dL, I2 = mean difference 93.0%, SD 71.4%)
    • 5 ICU studies:
      • -0.51 ± 1.59 g/dL (-3.63 to 2.62 g/dL, I2 = mean difference 83.7%, SD 96.4%)

Abstract:  Sang-Hyun. Accuracy of Continuous Noninvasive Hemoglobin Monitoring: A Systematic Review and Meta-Analysis. Anesth Analg 2014;119(2):332-346

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Observational Studies

Tanaka and colleagues completed a secondary analysis of a prospective, Brazilian, multicenter cohort study, examining the effects of early sedation strategies in 322 critically ill, mechanically ventilated patients, and found:

  1. deep sedation (GCS<9, 35.1%) was associated with
    • longer duration of ventilatory support
      • 7 (4 to 10) versus 5 (3 to 9) days, P = 0.041
    • increased tracheostomies
      • 38.9% versus 22%, P = 0.001
    • despite similar PaO2/FiO2 ratios & ARDS severity
  2. mortality rates were
    • ICU: 30.4%
    • hospital: 38.8%
  3. increased hospital mortality was associated with
    • age (OR 1.02; 95% CI 1.00 to 1.03),
    • Charlson Comorbidity Index >2 (OR 2.06; 95% CI 1.44 to 2.94),
    • Simplified Acute Physiology Score 3 (SAPS 3) score (OR 1.02; CI 95% 1.00 to 1.04)
    • severe ARDS (OR 1.44; CI 95% 1.09 to 1.91)
    • deep sedation (OR 2.36; CI 95% 1.31 to 4.25)

Full Text:  Tanaka. Early sedation and clinical outcomes of mechanically ventilated patients: a prospective multicenter cohort study. Critical Care 2014;18:R156

Papadopoulos et al reviewed single-centre data over 10 years aiming to assess risk factors associated with adverse outcomes in 360 consecutive cardiac surgical patients receiving extracorporeal life suppor for post-cardiotomy cardiogenic shock, and found:

  1. baseline data
    • mean age: 62±17 years
    • male: 76% 
    • mean preoperative ejection fraction: 35±16%
  2. ECLS details
    • cannulation
      • peripheral (90% )/ central thoracic (10%)
    • mean duration of ECLS: 7±1 days
    • intra-aortic balloon pump use: 22% 
  3. outcomes
    • ECLS weaning was successful in 58% 
    • 30% were discharged from hospital
    • main cause of death was sepsis (69%)
    • Kaplan Meier estimates for long-term survival were
      • at one year: 26±3% 
      • at 5 years: 22±2%
  4. complications included
    • major cerebrovascular events: 12% (bleeding 3%, embolic 9%)
    • limb ischaemia: 13%
    • gastrointestinal complications: 16%
    • renal replacement therapy: 61%
  5. independent risk factors for adverse outcome were
    1. prior cardiorespiratory resuscitation (OR: 4.1, 95% CI: 0.34 to 4.21, p=0.04)
    2. pH <7.1 (OR: 2.8, 95% CI: 0.45 to 3.28, p=0.01)
    3. serum lactate >120 mg/dL (OR: 2.6, 95% CI: 0.75 to 2.96, p< 0.01)
    4. noradrenaline dosage >0.5 µg/kg/min (OR: 2.4, 95% CI: 0.35 to 2.92, p=0.02)
    5. age >75 years (OR: 2.0, 95% CI: 0.41 to 2.88, p=0.02)

Abstract:  Papadopoulos. Risk factors associated with adverse outcome following extracorporeal life support: analysis from 360 consecutive patients. Perfusion 2014;epublished July 21st 

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Additional Studies

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Guidelines & Positional Statements 


Study Critiques

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Case Reports



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Clinical Review Articles













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I hope you find these brief summaries and links useful.

Until next week