Newsletter 135 / July 6th 2014




Welcome to the 135th 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.

This week's research studies include randomized controlled trials on red cell management in closed head injury, and fluid loading regimens for spinal anaesthesia in elective Caesarean section; meta analyses on trauma-related red cell transfusion, steroid administration to brain-dead potential organ donors, and early tracheostomy; and observational studies on timing of adrenaline administration in cardiac arrest, UK cardiac arrest data, and massive transfusion outcomes. Additional studies investigate traumatic brain injury-associated coagulopathy, burn resuscitation endpoints, Irish anaesthetic-surgical out-of-hours activity and accidental awareness in NAP5, biomarkers for acute kidney injury and cardiac arrest in PICU.

There is a single position statement (plus technical report) on managing a child's death in the emergency department, as well as several non-clinical editorials, including papers on assisted death and publishing rigor. There are a host of commentary articles, including the latest issue of ICU management. 

Amongst the clinical review articles are papers on therapeutic hypothermia for neuroprotection, extra-corporeal life support, post cardiac arrest management, swallowing disorders in tracheostomised patients, drug-induced autoimmune liver disease, antiplatelet agents, polymyxin B hemoperfusion, sepsis-related DIC, damage control surgery, patient deteriorization monitoring and preoperative risk assessment.  The beginning of each month marks the addition of recently made open access articles from the major critical care journals, with links to 30 articles from the American Journal of Respiratory and Critical Care Medicine, Chest, Critical Care, Anesthesia & Analgesia, British Journal of Anaesthesia, Anaesthesia and Anaesthesia and Intensive Care. There is also a single non-clinical review article addressing overdiagnosis and overtreatment.

Continuing on the theme of highlighting excellent open access critical care journals, the topic for This Week's Papers is a selection of articles from Annals of Intensive Care, the official journal of the French Society of Intensive Care, starting with a paper on hemodynamic parameters to guide fluid therapy in tomorrow's Paper of the Day.

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Critical Care Reviews Meeting 2015

Preparations are in full swing for the 2015 Critical Care Reviews Meeting, held in association with the Northern Ireland Intensive Care Society. Next year's meeting will be held on Friday January 23rd, again at the Galgorm Resort and Spa, outside Belfast, Northern Ireland. The theme of the meeting is to discuss the major research of the previous 12 months, where we try to answer a single question - should we be implementing the results of this study? In addition to a host of local intensivists critiquing major randomized controlled trials from 2014, we are fortunate to have the primary investigators from some of the biggest RCTS of the year join us.

Niklas Nielsen will discuss one of the "hottest" studies in the past decade - TTM; in the year of the early goal directed studies, Kathy Rowan will discuss her soon-to-publish studies, the UK ProMISe trial (the 3rd of the EGDT studies of the year), as well as CALORIES, a massive enteral versus parenteral nutrition study. Following on from SAILS, Danny McAuley will discuss his soon-to-publish HARP-2 study (statins in ARDS).  This makes the meeting one of the most topical events you could attend. In addition, Eddy Fan, head of ECMO at Toronto General, will participate in a perioperative session, where he will be joined by Eamon McCoy, inventor of the McCoy laryngoscope. John Hinds, of cricolol fame, will be on hand to review some new evidence and distill his unique wisdom. 

Further details will follow over the next couple of months. If you enjoy this weekly newsletter, then you'll love the opportunity to discuss the major studies of 2014 in person; however, if you can't make it, then you'll still be able to benefit, as all talks will once again be made freely available online very shortly afterwards.  Please join us for another fantastic not-for-profit event, where the focus is on improving critical care, not making money.

SMACC Chicago

It pains me to point it out, but the SMACC Chicago conference beats the Critical Care Reviews Meeting hands down. In fact, it beats every meeting hands down. If you can make it to the USA next June 23rd to 26th, you're in for a fantastic time. 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.

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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Randomized Controlled Trials

Robertson and colleagues, using a factorial design, compared intravenous erythropoietin (500 IU/kg per dose, n=102) with saline (n=98), plus red cell transfusion at a threshold of either 7 g/dL (n=99) or 10 g/dL (n=101), on Glasgow Outcome Scale score at 6 months postinjury, in 200 patients within 6 hours of closed head injury and unable to follow commands. Erythropoietin or placebo was initially dosed daily for 3 days and then weekly for 2  weeks (group 1, n = 74). The protocol was subsequently amended to (I think, it's remarkably poorly described) a single erythropoietin dose, possibly followed by further doses at 1 and 2 weeks if the patient was still in ICU (n=126). The authors found:

  1. no interaction between erythropoietin and hemoglobin transfusion threshold
  2. no statistical improvement on favorable outcome rate (dichotomized as favorable (good recovery and moderate disability) or unfavorable (severe disability, vegetative, or dead))
    • between placebo and erythropoietin
      • placebo: 38.2%; 95% CI 28.1% to 49.1%
      • erythropoietin
        • first dosing regimen:  48.6%; 95% CI 31.4% to 66.0%, P =0.13
        • second dosing regimen: 29.8%; 95% CI 18.4% to 43.4%; P  < 0.001
    • between haemoglobin transfusion thresholds
      • 7 g/dL:  42.5%
      • 10 g/dL: 33.0%
        • 95% CI for the difference −0.06 to 0.25, P = 0.28
  3. the 10 g/dL transfusion threshold was associated with a
    • higher incidence of thromboembolic events (21.8% vs 8.1%; odds ratio 0.32, 95% CI 0.12 to 0.79; P = 0.009)

Conclusion: In a two centre, factorial, randomized controlled trial, in patients with closed head injury, neither erythropoietin administration nor red blood cell transfusion maintaining a haemoglobin level of ≥10 g/dL versus ≥ 7 g/dL ,were statistically associated with improved outcomes, with the higher haemoglobin level associated with more thrombotic events.

Abstract:  Robertson. Effect of Erythropoietin and Transfusion Threshold on Neurological Recovery After Traumatic Brain Injury:  A Randomized Clinical Trial. JAMA 2014;312(1):36  

In a multicentre, randomized, double-blind study, Mercier and colleagues compared two fluid preloading regimens, (group 1: 500 ml 6% hydroxyethyl starch (130/0.4) plus 500 ml Ringer's lactate; group 2: 1000 ml Ringers lactate), in 167 healthy parturients undergoing elective Caesarean delivery under spinal anaestesia and also receiving phenylephrine-based prophylaxis, and found:

  1. the combined HES / RL preloading regimen was associated with
    • lower incidences (P=0.025) (1° outcome)
      • hypotension (36.6% vs 55.3%)
      • symptomatic hypotension (3.7% vs 14.1%)
    • no statistically significant difference in
      • total phenylephrine requirements [median (range): HES/RL: 350 (50–1800) vs RL: 350 (50–1250) µg]
      • decrease in maternal haemoglobin value the day after surgery  [HES/RL: 1.2 (1.0) vs RL: 1.0 (0.9) g dl−1]
      • neonatal outcomes
  2. there was no detectable placental transfer of HES in six umbilical cord blood samples

Conclusion: in a small, multicentre, randomized controlled trial in healthy parturients undergoing elective Caesarean delivery under spinal anaesthesia and receiving phenylephrine-based prophylaxis, a mixed hydroxyethyl starch / Ringer's lactate preloading regimen improved prevention of both hypotension and symptomatic hypotension, when compared with to a Ringer's lactate only regimen.

Abstract:  Mercier. 6% Hydroxyethyl starch (130/0.4) vs Ringer's lactate preloading before spinal anaesthesia for Caesarean delivery: the randomized, double-blind, multicentre CAESAR trial. Br J Anaesth 2014;epublished June 26th

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Meta Analyses

Patel et al pooled data from 40 observational studies to test for an association between red cell transfusion and mortality, plus other outcomes, in the trauma population, and found in studies adjusting for important confounders:

  1. red cell transfusion was associated with
    • each additional unit of transfused red blood cells increased the odds of
      • mortality (OR 1.07, 95% CI 1.04 to 1.10, I2 82.9%; 9 Studies)
      • multi-organ failure (OR 1.08, 95% CI 1.02 to 1.14, I2 95.9%; 3 studies) 
      • ARDS/ALI (OR 1.06, 95% CI 1.03 to 1.10, I2 0%; 2 studies)

Conclusion:  In a trauma setting, red cell transfusion is associated with worsened mortality, and increased liklihood of developing multi-organ failure or ARDS.

Abstract:  Patel. Risks associated with red blood cell transfusion in the trauma population, a meta-analysis. Injury 2014;epublished May 24th

Dupuis et al reviewed data from 11 randomized controlled trials and 14 observational studies, testing the efficacy and safety of corticosteroids in brain-dead potential organ donors, and found:

  1. the overall quality of studies was poor, with high risks of confounding
  2. significant heterogeneity prevented calculation of pooled estimates of outcome measures 
  3. methylprednisolone was the most commonly used corticosteroid, usually at a fixed dose between 1 and 5 g
  4. in randomized controlled trials
    • 10 out of the 11 trials yielded neutral results
  5. in observational studies
    • use of corticosteroids generally resulted in improved
      • donor haemodynamics and oxygenation status
      • organ procurement
      • recipient and graft survival

Conclusion: Evidence is weak to support the administration of corticosteroids in brain-dead potential organ donors

Abstract:  Dupuis. Corticosteroids in the management of brain-dead potential organ donors: a systematic review. Br J Anaesth 2014;epublished June 30th

Siempos et al pooled data from 13 randomised controlled trials (n=2,434; 800 deaths) comparing early tracheostomy (performed ≤ 1 week after intubation) with late (> 1 week after initiation of mechanical ventilation) or no tracheostomy, and found:

  1. early tracheostomy was associated with
    • lower ICU mortality
      • OR 0·72, 95% CI 0·53 to 0·98; p=0·04
      • 18% relative risk reduction for mortality
      • 5% absolute improvement in survival (65% to 70%)
      • persisting in 8 trials (n=1,934; 663 deaths) with a low risk of bias
        • OR 0·68, 95% CI 0·49 to 0·95; p=0·02
  2. no statistically significant difference in
    • 1-year mortality (n=1,529, 3 trials, 788 deaths)
      • early tracheostomy RR 0·93, 95% CI 0·85 to 1·02; p=0·14

Conclusion:  early tracheostomy is statistically associated with lower ICU mortality, not 1 year mortality

Full Text:  Siempos. Effect of early versus late or no tracheostomy on mortality of critically ill patients receiving mechanical ventilation: a systematic review and meta-analysis. Lancet Respir Med 2014;epublished June 26th     (free registration required)

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Observational Studies

Donnino et al completed a post hoc registry analysis of 119,978 adults from 570 hospitals, investigating if earlier administration of adrenaline in patients with non-shockable cardiac arrest rhythms is associated with increased return of spontaneous circulation, survival, and neurologically intact survival, and found:

  1. initial rhythm
    • asystole (55%) 
    • pulseless electrical activity (45%)
  2. almost 80% were excluded for various reasons
    • 83,490 because the arrest took place in the emergency department, intensive care unit, or surgical or other specialty unit
    • 10,775 because of missing or incomplete data
    • 524 as they had a repeat cardiac arrest
    • 85 as they received vasopressin before the first dose of adrenaline
  3. the main study population was
    • n=25,095
    • mean age 72 years
    • 57% male
  4. median time to administration of the first dose of epinephrine was 3 minutes (IQR 1-5 minutes)
  5. there was a stepwise decrease in survival with increasing interval of time to adrenaline (analyzed by three minute intervals)
    • 1-3 minutes (reference group): adjusted odds ratio 1.0
      • 4-6 minutes: aOR 0.91 (95% CI 0.82 to 1.00; P=0.055)
      • 7-9 minutes: aOR 0.74 (95% CI 0.63 to 0.88; P<0.001) 
      • >9 minutes 0.63 (95% CI 0.52 to 0.76; P<0.001)
      • a similar stepwise effect was observed across all outcome variables

Conclusion: In a post hoc registry study, delayed administration of adrenaline during in-hospital cardiac arrest with non-shockable rhythms was associated with decreased survival

Full Text:  Donnino. Time to administration of epinephrine and outcome after in-hospital cardiac arrest with non-shockable rhythms: retrospective analysis of large in-hospital data registry. BMJ 2014;348:g3028

Nolan et al, using prospectively collected data from the UK National Cardiac Arrest Audit database (144 acute hsoptials), evaluated the incidence of adult in-hospital cardiac arrest and survival to hospital discharge in 22,628 cardiac arrest patients, and found:

  1. incidence of adult in-hospital cardiac arrest: 1.6 per 1000 hospital admissions 
    • median across hospitals: 1.5 (IQR 1.2 to 2.2)
  2. incidence varied seasonally, peaking in winter
  3. presenting rhythms
    • shockable (ventricular fibrillation or pulseless ventricular tachycardia): 16.9%
    • non-shockable (asystole or pulseless electrical activity): 72.3%
  4. unadjusted survival to hospital discharge: 18.4%.
  5. rates of survival to hospital discharge
    • initial shockable rhythm: 49.0% 
    • initial non-shockable rhythm: 10.5%
    • varied substantially across hospitals

Conclusion:  In a large national UK registry, the incidence of adult in-hospital cardiac arrest was 1.6 per 1000 hospital admissions, more commonly presenting with a non-shockable rhythm, which was associated with a lower survival rate than cardiac arrests with a shockable rhythm.

Abstract:  Nolan. Incidence and outcome of in-hospital cardiac arrest in the United Kingdom National Cardiac Arrest Audit. Resuscitation 2014;85(8):987-992

Simms and colleagues performed a retrospective analysis of 151 massively transfused trauma patients surviving more than 30 minutes and undergoing surgery at a level 1 trauma center, and found:

  1. at 180 minutes
    • survivors (n=121, 80%) had received
      • higher mean infusion rates (mL/min) than non-survivors (n=30, 20%) of
        • fresh frozen plasma: 92.0 vs 33.7 mL/min;; p < 0.0001
        • platelets: 3.5 vs 1.1 mL/min;; p < 0.011
      • but not of
        • red cells:  71.9 vs 47.3 mL/min; p = 0.43
    • evaluating blood component mean infusion rates as mortality predictors
      • Cox regression model
        • red cell: hazard ratio 1.01; p = 0.054
        • fresh frozen plasma: HR 0.97; p < 0.0001
        • platelet: HR 0.75; p = 0.01
      • stepwise Cox regression
        • red cell: HR 1.00; p = 0.85
        • fresh frozen plasma: HR 0.97; p < 0.0001
        • platelet: HR 0.88; p = 0.24

Conclusion: In a retrospective, single centre study, higher mean infusion rates of fresh frozen plasma and platelets were associated with improved survival at 3 hours

Abstract:  Simms. Impact of Infusion Rates of Fresh Frozen Plasma and Platelets During the First 180 Minutes of Resuscitation. J Am Coll Surg 2014;epublished May 1st

Mitra and colleagues performed a single-centre, retrospective study over a six year period, evaluating outcomes after massive blood transfusion within the first 24 hours of major trauma, and found

  1. cohort
    • 5,915 patients with major trauma
    • 365 (6.2%; 95% CI 5.6 to 6.8) received a massive transfusion
  2. fewer major trauma patients received a massive transfusion over time
    • 8.2 to 4.4% (p<0.01)
  3. statistically significant changes in transfusion practice (p<0.01)
    • lower volumes of red cell transfusion 
    • higher ratios of fresh frozen plasma to red cells 
  4. no statistically significant change in measured outcomes over the study period
    • hospital mortality - 23%
    • unfavourable GOSE at 6-months - 52%
    • unfavourable GOSE at 12-months - 44%
  5. massive transfusion was
    • independently associated with
      • unfavourable outcomes at 6 months
        • adjusted OR 1.56; 95% CI 1.05 to 2.31
    • not independently associated with 
      • unfavourable outcomes at 12 months
        • adjusted OR 0.85; 95% CI 0.72 to 1.01

Conclusion:  In a retrospective, single-centre study, massive transfusion was treated with lower volumes of red cell transfusion, and higher transfusion ratios of fresh frozen plasma to red cells, without improvements in patient centred outcomes over a six year period.

Full Text:  Mitra. Long-Term Outcomes of Patients Receiving Massive Transfusion After Trauma. Shock 2014;epublished June 21st

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Additional Studies

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Guidelines and Position Statements



ICU Management









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Recently Made Open Access Articles from the Major Journals

American Journal of Respiratory and Critical Care Medicine


Guidelines & Position Statements



Case Reports

Critical Care




Anesthesia & Analgesia


British Journal of Anaesthesia




Anaesthesia and Intensive Care



Special Report

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Non-Clinical Review Articles 

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I hope you find these brief summaries and links useful.

Until next week