Newsletter 90 / August 25th 2013




Welcome to the 90th 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 interventional research studies include the long awaited publication of the HOPE-ICU trial (preliminary results were brought to you 8 months ago), as well as an investigation of plasma filtration in paediatric sepsis. Meta analyses examine ECMO, intravenous iron for anaemia and the effect size of single-centre studies. Observational studies address Middel East Respiratory Syndrome Coronavirus, infective endocarditis in the critically ill, ultra early thrombolysis in stroke, hyperoxia in traumatic brain injury and inodilators in cardiogenic shock.

There is just one guideline this week, from the American Thoracic Society, which focuses on community-acquired pneumonia. There are editorials on acute kidney injury and post-operative critical care, along with commentaries on haemoptysis, MERS-CoV, European research funding and medical education.

Amongst the clinical review articles are papers on septic encephalopathy, acute coronary syndrome, ARDS, hepatic encephalopathy, physiocochemical acid-base guided fluid management, perioperative anticoagulant and antiplatelet management, residual sepsis mortality, antibiotics, and renal dysfunction in burns. A single non-clinical review article questions the legality of research consent forms.

The topic for This Week's Papers is pharmacotherapy for ARDS, starting with a general paper from a colleague in tomorrow's Paper of the Day.

If you only have time to read one paper this week, try the article on the biotic effects of antibiotics, by Aminov and colleagues.


Critical Care Reviews Meeting 2014

For the second year, Critical Care Reviews will be hosting a meeting discussing the major critical care studies published in the past 12 months. The first event was a small evening meeting attended by over 100 local clinicians. Paralleling the growth of the website, the 2014 meeting year will be significantly bigger, with talks from major international guest speakers Prof Alistair Nichol (Dublin/Melbourne), Prof Mervyn Singer (London) and Prof John Marshall (Toronto), in addition to a host of local intensivists, as well as colleagues from microbiology, haematology and hepatology. This all day event will finish with an informal evening question and answers session with the guest speakers, followed by dinner.

It's on Friday January 24th, just outside Belfast, so if you're a drive or short flight away, it would be great to have you come along. Travel on Thursday, attend the meeting on Friday and see some of the local landmarks over the weekend, before returning home on Sunday evening after a great winter break. On Saturday visit the North Coast: the World Heritage site Giants Causeway, Carrick-a-Rede rope bridge, Dunluce Castle and Bushmills Distillary, the oldest Distillary in the world; while on Sunday experience Belfast: the new acclaimed Titanic Centre followed by a famous black taxi tour describing the troubled past of one of Europe's now most vibrant cities. CPD approval will be sought from the UK Royal College of Anaesthetists. The full programme and registration will open in a few weeks. Please feel free to contact me if you're thinking on making the trip - it would be great to hear from you.  



Randomized Controlled Trials

Lancet Respiratory Medicine:     Delirium

In a double-blind, placebo-controlled randomised trial comparing haloperidol (n=71) 2.5 mg IV 8 hourly, with 0.9% saline (n=70), regardless of coma or delirium status, in general critically ill mechanically ventilated patients within 72 hours of ICU admission, Page and colleagues found:

  1. no difference in the number of days alive, without delirium, and without coma (median 5 days [IQR 0—10] vs 6 days [0—11] days; p=0·53)
  2. Numerically more oversedation with haloperidol (11 patients versus 6)
  3. No difference in rates of QTc prolongation (haloperidol 7 patients versus placebo 6).
  4. No serious adverse events with haloperidol

Stroke:     Granulocyte Colony-Stimulating Factor

Ringelstein and colleagues completed a multinational, multicenter, randomized, placebo-controlled trial evaluating G-CSF (135 µg/kg IV over 72 hours) in 328 patients within 9 hours of a middle cerebral artery territory infarction and a National Institutes of Health Stroke Scale score range of 6 to 22, and found:

  1. no improvement in the primary endpoint of modified Rankin scale score at day 90
  2. no improvement in the secondary endpoint of National Institutes of Health Stroke Scale score at day 90
  3. no improvement in mortality, Barthel index, or infarct size at day 30
  4. a trend for reduced infarct growth
  5. increased leukocyte and monocyte counts

Abstract:  Ringelstein. Granulocyte Colony–Stimulating Factor in Patients With Acute Ischemic Stroke. Results of the AX200 for Ischemic Stroke Trial. Stroke 2013;epublished August 20th


Anesthesiology:     Ventilation Modes

Clavieras and colleagues completed a prospective, randomized, single-blind crossover study in 14 patients weaning from mechanical ventilation, comparing Intellivent, a fully closed-loop controlled mode of ventilation that automatically adjusts ventilation and oxygenation parameters, with pressure support ventilation, for two periods of 24 h, and found:

  1. improved oxygenation, with an increase in PaO2/FiO2 (mean ± SD) from 245 ± 75 at baseline to 294 ± 123 (P = 0.03) after 24 h of Intellivent
  2. increased coefficient of variation of inspiratory pressure and PEEP (median [IQR); 16 [11–21] and 15 [7–23]% versus 6 [5–7] and 7 [5–10]% 
  3. increased inspiratory pressure, PEEP, and FiO2 changes were adjusted significantly more often

Full Text:  Clavieras. Prospective Randomized Crossover Study of a New Closed-loop Control System versus Pressure Support during Weaning from Mechanical Ventilation. Anesthesiology 2013;119(3):631–641 


Critical Care & Resuscitation:     Paediatric Sepsis Plasma Filtration

Long and colleagues undertook a multi-centre randomised controlled trial in 48 infants and children with severe sepsis, comparing plasma filtration (n=25) with standard therapy (n=23), and found:

  1. early study termination due to poor recruitment
  2. no difference in the adjusted odds ratio for death with plasma filtration (1.20; 95% CI 0.23-6.20; P = 0.82)
  3. no difference in the median number of organ failures at day 7 (filtration group 2 [IQR 1-4] versus standard group 2 [IQR 1-3])
  4. two children in the filtration group required ECMO for 2.5 and 123 hours, and one child in the control group required ECMO for 45 hours.
  5. a median modified Glasgow outcome score at 6 months of 4 [IQR 2-6] in the plasma filtration group and 2 [IQR 1-4] in the control group

Abstract:  Long. A randomised controlled trial of plasma filtration in severe paediatric sepsis. Crit Care Resusc 2013;15(3):198-204


Meta Analysis

Journal of Critical Care:     ECMO

Zampieri et al performed a systematic review and meta analysis, including 1 randomized controlled trial and 2 observational case-control studies with severity-paired patients (total n=353), examining the effect of extracorporeal membrane oxygenation (n=179) for severe acute respiratory failure, and found:

  1. the most common reasons for acute respiratory failure were influenza H1N1 pneumonia (45%) and pneumonia (33%)
  2. ECMO was not associated with reduced hospital mortality (OR = 0.71; CI 95% 0.34 - 1.47, P = 0.358)
  3. modifying the analysis to an alternative severity-pairing method based on the two observational studies (n=478, n=228 receiving ECMO), ECMO was associated with reduced hospital mortality (OR 0.52, CI 95% 0.35 - 0.76, P < 0.001)

Abstract:  Zampieri. Extracorporeal membrane oxygenation for severe respiratory failure in adult patients: A systematic review and meta-analysis of current evidence. J Crit Care 2013;epublished August 15th 


British Medical Journal:     Intravenous Iron

Litton et al undertook a systematic review and meta-analysis of randomised controlled trials (72 trials, n=10,605) investigating the safety and efficacy of intravenous iron therapy, compared with oral iron or no iron, and found IV iron was associated with:

  1. an increase in haemoglobin concentration (standardised mean difference 6.5 g/L, 95% CI 5.1 g/L - 7.9 g/L)
  2. a reduced risk of requirement for red blood cell transfusion (risk ratio 0.74, 95% CI 0.62 - 0.88)
  3. an increased risk of infection (relative risk 1.33, 95% CI 1.10 - 1.64)

Full Text:  Litton. Safety and efficacy of intravenous iron therapy in reducing requirement for allogeneic blood transfusion: systematic review and meta-analysis of randomised clinical trials. BMJ 2013;347:f4822


Journal of Clinical Epidemiology:     Study Effect Size

Using data from 12 meta analysis (82 randomized controlled trials), Unverzagt et al evaluated whether reported trial characteristics are associated with treatment effects on all-cause mortality within critical care medicine, and found:

  1. single-center trials estimated a significant larger treatment effect compared with multicenter trials (ratio of odds ratios 0.64; 95% CI 0.47 - 0.87)
  2. treatment effect tended to be overestimated with selective reporting of preplanned end points.
  3. biases in different trial characteristics are unlikely to operate independently and may have modified these associations

The authors recommeded results from single-center trials should be cautiously used for decision making.

Abstract:  Unverzagt. Single-center trials tend to provide larger treatment effects than multicenter trials: a systematic review. Journal of Clinical Epidemiology 2013;epublished August 22nd


Observational Studies

Lancet Infectious Diseases:     MERS-CoV

Assiri and colleagues report epidemiological, demographic, clinical, and laboratory characteristics of 47 cases of sporadic, household, community, and health-care-associated Middle East respiratory syndrome coronavirus infections in Saudi Arabia between September 2012, and June 2013, and found:

  1. 77% were male (male:female ratio 3·3:1)
  2. 28 patients died (60% case-fatality rate, which rose with increasing age)
  3. only two of the 47 cases were previously healthy - 96% had underlying comorbid medical disorders, including diabetes (68%), hypertension (34%), chronic cardiac disease (28%) and chronic renal disease (49%)
  4. common symptoms at presentation were fever (98%), fever with chills or rigors (87%), cough (83%), shortness of breath (72%), and myalgia (32%)
  5. gastrointestinal symptoms were frequent, including diarrhoea (26%), vomiting (21%), and abdominal pain (17%)
  6. all patients had abnormal findings on chest radiography, ranging from subtle to extensive unilateral and bilateral abnormalities
  7. raised concentrations of lactate dehydrogenase (49%) and aspartate aminotransferase (15%), as well as thrombocytopenia (36%) and lymphopenia (34%).

Abstract:  Assiri. Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study. Lancet Infectious Diseases 2013;13(9):752-761


Lancet:     MERS-CoV

Based on WHO summary data and subsequent reports, including 55 of the 64 laboratory-confirmed cases of MERS-CoV reported as of June 21, 2013, Breban et al estimated virus transmissibility and the epidemic potential of MERS-CoV, and compared the results with similar findings obtained for prepandemic SARS. Considering two scenarios, depending on the interpretation of the MERS-CoV cluster-size data, they found:

  1. in a pessimistic scenario, MERS-CoV basic reproduction number (R0) was estimated at 0·69 (95% CI 0·50—0·92), which contrasts with a R0 for prepandemic SARS-CoV of 0·80 (95% CI 0·54—1·13)
  2. in an optimistic scenario, MERS-CoV R0 was estimated at 0·60 (95% CI 0·42—0·80).
  3. modifying the pessimistic scenario based on recent implementation of effective contact tracing and isolation procedures, eight or more secondary infections caused by the next index patient would translate into a 5% or higher chance that the revised MERS-CoV R0 would exceed 1, meaning that MERS-CoV might have pandemic potential

Abstract:  Breban. Interhuman transmissibility of Middle East respiratory syndrome coronavirus: estimation of pandemic risk. Lancet 2013;382(9893):694-699


European Heart Journal:     Infective Endocarditis 

Using data, prospectively collected between 2007 and 2008, from 198 French critically ill patients with infective endocarditis,  Mirabel and colleagues found:

  • 69% were dead at a median follow-up time of 59.5 months.
  • Characteristics significantly associated with mortality were:
    • Sepsis-related Organ-Failure Assessment (SOFA) score at ICU admission; (SOFA 5–9: HR 1.43, 95% CI 0.79–2.59); (SOFA 10-14: HR 2.01, 95% CI 1.05–3.85); (SOFA 15–20: HR 3.53, 95% CI 1.75–7.11); (reference category SOFA 0–4, P = 0.003)
    • prosthetic mechanical valve IE (HR 2.01, 95% CI 1.09–3.69, P = 0.025)
    • vegetation size ≥15 mm (HR 1.64, 95% CI 1.03–2.63, P = 0.038)
    • cardiac surgery;  for surgery ≤1 day after IE diagnosis (HR 0.33, 95% CI 0.16–0.67),  for surgery 2–7 days after IE diagnosis (HR 0.61, 95% CI 0.29–1.26); for surgery >7 days after IE diagnosis (HR 0.42, 95% CI 0.21–0.83), reference category no surgery (P = 0.005)
  • 52% underwent cardiac surgery after a median time of 6 (16) days.
  • Independent predictors of surgical intervention on multivariate analysis were:
    • age ≤ 60 years (OR 5.30, 95% CI 2.46–11.41, P < 0.01)
    • heart failure (OR 3.27, 95% CI 1.03–10.35, P = 0.04)
    • cardiogenic shock (OR 3.31, 95% CI 1.47–7.46, P = 0.004),
    • septic shock (OR 0.25, 95% CI 0.11–0.59, P = 0.002)
    • immunosuppression (OR 0.15, 95% CI 0.04–0.55, P = 0.004)
    • diagnosis before or within 24 h of ICU admission (OR 2.81, 95% CI 1.14–6.95, P = 0.025)
  • SOFA score calculated the day of surgery was the only independently associated factor with long-term mortality (SOFA 5–9: HR 1.59, 95% CI 0.77–3.28); (SOFA 10-14:  HR 3.56, 95% CI 1.71–7.38); (SOFA 15–20: HR 11.58, 95% CI 4.02–33.35), (reference category SOFA 0–4; P < 0.0001)
  • Surgical timing was not associated with post-operative outcomes.
  • Of the 158 patients with a theoretical indication for surgery, the 58 deemed not fit had a 95% mortality rate

Abstract:  Mirabel. Long-term outcomes and cardiac surgery in critically ill patients with infective endocarditis. Eur Heart J 2013;epublished August 20th 


Stroke:     Early Thrombolysis

Using prospectively collected data from a large European multi-center cohort (n=6856), Strbian and colleagues investigated whether extra benefit of treatment within 90 minutes from symptom onset (ultra-early treatment) is uniform across predefined stroke severity subgroups, as compared with later thrombolysis, and found:

  1. ultra-early treatment was not associated with mortality
  2. as a continuous variable, shorter onset-to-treatment time was significantly associated with excellent outcome (P < 0.001)
  3. 20% had onset-to-treatment time ≤ 90 minutes, with this cohort having a lower frequency of intracranial hemorrhage
  4. adjusted onset-to-treatment time ≤ 90 minutes was associated with excellent outcome in patients with National Institutes of Health Stroke Scale 7 to 12 (odds ratio 1.37, 95% CI 1.11–1.70, P = 0.004), but not in patients with baseline National Institutes of Health Stroke Scale > 12 (OR 1.00; 95% CI 0.76–1.32; P = 0.99) or baseline National Institutes of Health Stroke Scale 0 to 6 (OR 1.04, 95% CI 0.78–1.39; P = 0.80)
  5. In the cohort with a baseline National Institutes of Health Stroke Scale 0 to 6 an independent association (OR 1.51; 95% CI 1.14–2.01; P < 0.01) was found when considering modified Rankin scale 0 as outcome (to overcome the possible ceiling effect from spontaneous better prognosis of patients with mild symptoms)

Abstract:  Strbian. Ultra-Early Intravenous Stroke Thrombolysis: Do All Patients Benefit Similarly? Stroke 2013;epublished August 22nd


Critical Care:     Hyperoxia

Using the the Finnish Intensive Care Consortium database (n=1,116), Raj et al investigated the independent relationship between hyperoxemia and long-term mortality in patients with moderate-to-severe traumatic brain injury, and found:

  • 16% were hypoxaemic (< 10.0 kPa), 51% normoxaemic (10.0-13.3 kPa) and 33% hyperoxaemic (> 13.3 kPa) during the first 24 hours of ICU admission
  • 6-month mortality was 39%
  • A significant association between hyperoxaemia and a decreased risk of mortality was found in univariate analysis (P= 0.012)
  • after adjusting for markers of illness severity, hyperoxaemia showed no independent relationship with 6-month mortality:
    • hyperoxaemia versus normoxaemia: OR 0.88, 95% CI 0. 63 - 1.22, P = 0.43
    • hyperoxaemia versus hypoxaemia: OR 0.97, 95% CI 0.63 - 1.50, P = 0.90   

Full Text:  Raj. Hyperoxemia and long-term outcome after traumatic brain injury. Critical Care 2013;17:R177


PLoS One:     Cardiogenic Shock

Combining data from three observational cohorts, totaling 988 patients with severe cardiogenic shock, using a propensity score model, Pirracchio et al compared therapy with an inopressor alone with a combination of inopressor plus inodilator, and found:

  • 643 (65.1%) died within the first 30 days
    • inopressors alone: 293 (72.0%)
    • inopressors and inodilators: 350 (60.0%)).
  • after propensity score weighting, and estimated by fitting a weighted Cox regression model, inopressor plus inodilator therapy was associated with an improved short-term mortality (HR 0.66, 95% CI 0.55–0.80) compared to inopressors alone

Full Text:  Pirracchio. The Effectiveness of Inodilators in Reducing Short Term Mortality among Patient with Severe Cardiogenic Shock: A Propensity-Based Analysis. PLoS ONE 2013;8(8):e71659



American Journal of Respiratory and Critical Care Medicine:     Community-Acquired Pneumonia



Blood Purification:     Acute Kidney Injury


Anesthesiology:     Postoperative Critical Care



Interactive Cardiovascular and Thoracic Surgery:     Haemoptysis 


The Lancet:     MERS-CoV


The Lancet:     European Research Funding


Journal of the American Medical Association:     Continuing Medical Education


Review - Clinical


Anaesthesiology Intensive Therapy:     Sugammadex


Current Neurology and Neuroscience Reports:     Septic Encephalopathy



African Journal of Emergency Medicine:     Acute Coronary Syndrome


Journal of the American Heart Association:     Gene Therapy for Circulatory Disease


Seminars in Cardiothoracic and Vascular Anaesthesia:     Aortic Arch Surgery



BMC Medicine:     ARDS


Lancet Respiratory Medicine:     ARDS


Liver International:     Liver Transplantation



Anaesthesiology Intensive Therapy:     Physiocochemical Guided Fluid Management



Journal of the American Heart Association:     Testosterone



Deutsches Ärzteblatt International:     Perioperative Anticoagulants and Antiplatelets  




I hope you find these brief summaries and links useful.

Until next week