Newsletter 93 / September 15th 2013




Welcome to the 93rd 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, editorials and commentaries from over 300 clinical and scientific journals.

This week's research studies include randomized trials investigating pentoxyfylline for acute alcoholic hepatitis, LiDCO-guided fluid management in burns, ProAQT-guided perioperative fluid management, whole blood administration in trauma, intensive glycaemic control in acute coronary syndromes, as well as follow up studies on CRASH 2 (an economic evaluation) and IABP-SHOCK II (12 month follow up). Meta analyses examine oral anticoagulants and antiplatelets for the prevention of venothromboembolism, mono- or dual-antiplatelet therapy in ischaemic stroke, colony-stimulating factor for stroke and perioperative haemodynamic management. Observational studies look at cardiac output monitoring, maternal sepsis, futile critical care therapy,  cardiac arrest progosis, prehospital cardiac arrest, antimicrobial de-escalation, intermediate lactate values in sepsis and culture-negative versus culture-positive sepsis.

This week's there are no guidelines or editorials, although there are a number of commentaries, focusing on medicare spending, neuromuscular blockade, irisinaemia, tuberculosis, research misconduct and the future hospital commission.

Amongst the clinical review articles are papers on ischaemic stroke, peripartum cardiomyopathy, spinal cord injury, COPD, bleeding peptic ulcer, autoimmune hepatitis, new oral anticoagulants, imaging in renal trauma, colistin and dengue virus.

The topic for This Week's Papers is cerebral haemorrhage, starting with a general paper on the subject in tomorrow's Paper of the Day.


There are two meetings coming up that might be of interest to you:

Critical Care Reviews Meeting January 24th, 2014 - Belfast, Northern Ireland

  • If you are in Ireland or Great Britain (or a short flight away), Critical Care Reviews will be hosting it's second meeting outside Belfast, Northern Ireland. It's an all-day event with a fantastic programme consisting of local intensivists, local non-critical care specialists, and major international guest speakers. Registration opens first week in October.

SMACC GOLD March 19-21st, 2014 Gold Coast, Queensland, Australia

  • This major international conference, also in it's second year, is a must for those active in the online critical care community. Webmasters of the most prominent critical care websites and blogs will descend on the beautiful Gold Coast for an amazing get together of like-minded people in a totally different style of conference. Registration opened today.


Interview with Dr Minh Le Cong
  • If you'd like to hear more about Critical Care Reviews, check out this podcast of me being interviewed by Dr Minh Le Cong of the Australian Royal Flying Doctor Service, and posted Tuesday on Minh's excellent pre-hospital and retrieval PHARM website. We also discuss the above two meetings, open access publications, peer review for FOAMed (free open-access medical education) resources, the CRASH-2 trial, plus some other topics.



Randomized Controlled Trials

Journal of the American Medical Association:     Severe Alcoholic Hepatitis

Mathurin and colleagues performed a multicenter, randomized, double-blind trial in 270 heavy drinkers with severe biopsy-proven alcoholic hepatitis, comparing a combination (n=133) of prednisolone (40 mg OD) and pentoxifylline (400 mg TID) with a combination (n=137) of prednisolone (40 mg OD) with matching placebo for 28 days, and found no difference between groups in:

  1. 6 month survival (prednisolone-pentoxifylline 69.9% (95% CI 62.1%-77.7%) versus prednisolone-placebo 69.2% (95% CI 61.4%-76.9%); p=0 .91)
  2. response to therapy at 7 days, as assessed by the Lille model (prednisolone-pentoxifylline 0.41 (95% CI 0.36-0.46) versus prednisolone-placebo 0.40 (95% CI 0.35-0.45); p=0 .80)
  3. a trend for reduced incidence of hepatorenal syndrome at 6 months (pentoxifylline-prednisolone 8.4% (95% CI 4.8%-14.8%) versus placebo-prednisolone groups 15.3% (95% CI, 10.3%-22.7%); p=0.07)

Abstract:  Mathurin. Prednisolone With vs Without Pentoxifylline and Survival of Patients With Severe Alcoholic HepatitisA Randomized Clinical Trial. JAMA 2013;310(10):1033-1041


Journal of Burn Care & Research:     Burns Fluid Therapy

Tokarik et al performed a small, pilot, randomized controlled trial in 21 patients with burns of between 10% and 75%, comparing LiDCO controlled optimization of volume resuscitation with standard therapy and found LiDCO guided therapy was associated with:

  1. a smaller volume of infused crystalloids (p=0.04)
  2. an approximate 10% lower total fluid balance

Abstract:  Tokarik. Fluid Therapy LiDCO Controlled Trial-Optimization of Volume Resuscitation of Extensively Burned Patients through Noninvasive Continuous Real-Time Hemodynamic Monitoring LiDCO. Journal of Burn Care & Research 2013;34(5):537-542 


Critical Care:     Perioperative Goal Directed Haemodynamic Therapy

Salzwedel and colleagues completed a mutli-centre, randomized controlled trial in 160 patients undergoing elective major abdominal surgery and compared goal-directed haemodynamic management based on radial artery derived data via the non-invasive ProAQT (Professional Advanced Flow Trending, n=79) device, versus control therapy (n=81), and found:

  1. a reduced number of complications with ProAQT guided therapy
    • total complications: 72 versus 52; p=0.038
    • infectious complications: 13 versus 26; p=0.023
  2. no differences in
    • number of days post-operatively for return of bowel movement (ProAQT 3 versus control 2 days; p = 0.316)
    • duration of post anesthesia care unit stay (ProAQT 180 versus control 180 minutes, p = 0.516)
    • length of hospital stay (ProAQT 11 days versus control 10 days; p=0.929)

Abstract:  Salzwedel. Perioperative goal-directed hemodynamic therapy based on radial arterial pulse pressure variation and continuous cardiac index trending reduces postoperative complications after major abdominal surgery: a multi-center, prospective, randomized study. Critical Care 2013;17:R191 


Annals of Surgery:     Whole Blood Transfusion

Cotton and colleagues completed a single-centre, randomized trial in 107 severely injured trauma patients predicted to receive massive transfusion, comparing modified whole blood (n=55) transfusion with blood component (n=52) transfusion, with all patients also receiving 1 unit of platelets for every 6 units of modified whole blood or 6 units of red blood cells plus 6 units plasma, and found:

  1. no difference in transfusion in the intention-to-treat analysis
  2. in a sensitivity analysis, excluding patients with severe brain injury, modfied whole blood therapy was associated with reduced transfusions at 24 hours of
    • red blood cells (median 3 versus 6, p=0.02)
    • plasma (4 vs 6, p=0.02)
    • platelets (0 vs 3, p=0.09)
    • total products (11 vs 16, p=0.02)

Abstract:  Cotton. A Randomized Controlled Pilot Trial of Modified Whole Blood versus Component Therapy in Severely Injured Patients Requiring Large Volume Transfusions. Annals of Surgery 2013;258(4):527-533


JAMA Internal Medicine:     Glycaemic Control in Acute Coronary Syndrome

De Mulder et al completed a single-center, prospective, open-label, randomized trial in 294 non-diabetic patients with an acute coronary syndrome due to undergo PCI (93.6% received PCI) and an admission plasma glucose level of 140 to 288 mg/dL (7.7 - 16 mmol/L), comparing intensive glycaemic control (85 to 110 mg/dL; 4.7 - 6.1 mmol/L) with standard therapy, and found intensive glycaemic control was associated with

  1. no difference in median biomarker levels
    • IGC: hsTropT72 1197 ng/L (25th and 75th percentiles of distribution, 541-2296 ng/L) versus control: 1354 ng/L (530-3057 ng/L) (p=0.41)
    • IGC: AUC–CK-MB 2372 U/L (1242-5004 U/L) versus control: 3171 U/L (1620-5337 U/L) (p= 0.18)
  2. no difference in median extent of myocardial injury measured by myocardial perfusion scintigraphy (2% vs 4%; p=0.07)
  3. increased rates of death or a spontaneous second myocardial infarction prior to discharge (5.7% versus 0.7%; p=0.04)
  4. severe hypoglycemia (<50 mg/dL) was rare (n=13)

Abstract:  de Mulder. Intensive Glucose Regulation in Hyperglycemic Acute Coronary Syndrome:  Results of the Randomized BIOMarker Study to Identify the Acute Risk of a Coronary Syndrome–2 (BIOMArCS-2) Glucose Trial. JAMA Intern Med 2013;epublished September 9th   


Health Technology Assessment:     CRASH-2 Economic Evaluation

Roberts et al completed an economic assessment of CRASH-2, a large, international, multi-centre, randomized, controlled trial in 20,211 adult trauma patients with, or at risk of, significant bleeding who were within 8 hours of injury, comparing tranexamic acid (1 g over 10 minutes followed by 1 g over 8 hours) or matching placebo, and found:

Tranexamic acid administration was associated with

  1. an estimated saving of 755 life years per 1000 trauma patients treated in the UK, when administered within 3 hours of injury
  2. an estimated cost of $30,830 per 1000 patients
  3. an incremental cost of giving tranexamic acid, compared with not giving tranexamic acid, of $48,002
  4. an incremental cost per life year gained of $64

Full Text:  Roberts. The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients. Health Technol Assess 2013;17(10):1-79


Lancet:     Intra-Aortic Balloon Pump  

Thiele and colleagues report the 12 months outcomes from the IABP-SHOCK II trial, a prospective, open-label, multicenter randomized controlled trial in 600 patients with acute myocardial infarction complicated by cardiogenic shock, comparing intra-aortic balloon counterpulsation (IABP, n=301) with no IABP (n=299), and, in the 595 subjects completing 12 month follow-up, they found:

  1. no differences in: 
    • mortality (IABP 52% versus control 51%; relative risk 1·01, 95% CI 0·86 - 1·18; p=0·91)
    • recurrent revascularisation (IABP RR 0·91, 0·58 - 1·41, p=0·77)
    • stroke (IABP RR 1·50, 0·25 - 8·84, p=1·00)
    • quality-of-life measures including mobility, self-care, usual activities, pain or discomfort, and anxiety or depression
  2. a trend towards increased risk for reinfarction (IABP RR 2·60, 95% CI 0·95 - 7·10, p=0·05)

Abstract:  Thiele. Intra-aortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock (IABP-SHOCK II): final 12 month results of a randomised, open-label trial. Lancet 2013;epublished September 2nd


Meta Analysis

British Journal of Anaesthesia:     Perioperative Haemodynamic Management

Grocott and colleagues reviewed 31 randomized controlled trials (n=5,292) investigating perioperative goal-directed therapy by increasing blood flow using fluids with or without inotropes/vasoactive, and found:

  1. no difference in mortality at the longest follow-up (controls 10.8% versus intervention 8.9%; RR 0.89; 95% CI 0.76–1.05; P=0.18)
  2. the results were sensitive to analytical methods and withdrawal of studies with methodological limitations
  3. the intervention was associated with reduced rates of renal failure, respiratory failure, wound infections, number of patients with complications and length of hospital stay by 1.16 days
  4. the intervention was associated with no effect on rates of arrhythmia, myocardial infarction, congestive cardiac failure, venous thrombosis, other types of infections and critical care length of stay

Abstract:  Grocott. Perioperative increase in global blood flow to explicit defined goals and outcomes after surgery: a Cochrane Systematic Review. Br J Anaesth 2013;111:535-548


British Medical Journal:     Pharmacological Venothromboembolism Prophylaxis

Castellucci and colleagues pooled 12 randomized, controlled studies (n=11,999 for efficacy, n=12,167 for safety), examining the efficacy and safety of various oral anticoagulants (dabigatran, rivaroxaban, apixaban, and vitamin K antagonists) and antiplatelet agents (aspirin) for the secondary prevention of venous thromboembolism, and found:

  1. all treatments reduced the risk of recurrent venous thromboembolism
  2. compared with placebo or observation
    • vitamin K antagonists (target INR 2.0-3.0) showed the highest risk difference (odds ratio 0.07; 95% credible interval 0.03 to 0.15) 
    • aspirin showed the lowest risk difference (0.65; 0.39 to 1.03).
  3. risk of major bleeding was higher with a standard adjusted dose of vitamin K antagonists (5.24; 1.78 to 18.25) than with placebo or observation
  4. fatal recurrent venous thromboembolism and fatal bleeding were rare

Full Text:  Castellucci. Efficacy and safety outcomes of oral anticoagulants and antiplatelet drugs in the secondary prevention of venous thromboembolism: systematic review and network meta-analysis. BMJ 2013;347:f5133


Stroke:     Colony-Stimulating Factors for Stroke

England et al reviewed data from 11 studies (n= 1,275) investigating the effects of colony-stimulating factors in stroke, and found:

  1. Erythropoietin therapy (3 studies, n=782), was associated with
    • increased mortality (odds ratio 1.98; 95% CI 1.19–3.3; P=0.009)
    • no effect on infarct volume
    • a nonsignificant increase in serious adverse events
    • an increase in red cell count with no effect on platelet or white cell count
  2. G-CSF (8 studies, n=548) had no effect on
    • infarct size
    • early impairment (mean difference −0.4; 95% CI −1.82 to 1.01; P=0.58)
    • functional outcome
    • G-CSF significantly elevated white cell count and CD34+ cell count

Full Text:  England. Colony-Stimulating Factors for the Treatment of Stroke. Stroke 2013;epublished September 12th


Circulation:     Anti-Platelet Therapy

Wong and colleagues evaluated 14 studies (n=9,012) investigating dual- versus mono- antiplatelet therapy in patients with acute non-cardioembolic ischaemic stroke or transient ischaemic attack, with treatment initiated within 3 days of ictus, and found, compared with monotherapy, dual-antiplatelet therapy:

  1. significantly reduced the risk of
    • stroke recurrence (RR 0.69, 95% CI 0.60-0.80, P<0.001) 
    • composite outcome of stroke, TIA, acute coronary syndrome and all death (RR 0.71, 95% CI 0.63-0.81, P<0.001) 
  2. with no significant effect on the risk of major bleeding (RR 1.35, 95% CI 0.70-2.59, P=0.37)

Abstract:  Wong. Early Dual versus Mono Antiplatelet Therapy for Acute Non-Cardioembolic Ischemic Stroke or Transient Ischemic Attack: An Updated Systematic Review and Meta-Analysis. Circulation 2013;epublished September 12th


Observational Studies

Anesth Analg:    Maternal Sepsis

Using data from the Nationwide Inpatient Sample, comprising 44,999,260 hospitalizations for delivery, Bauer and colleagues characterized maternal sepsis morbidity and mortality in the USA from 1998 to 2008, and found:

  1. sepsis complicated 1:3,333 (95% CI 1:3151–1:3540) deliveries
  2. severe sepsis complicated 1:10,823 (95% CI 1:10,000–1:11,792) deliveries
  3. sepsis-related death complicated 1:105,263 (95% CI 1:83,333–1:131,579) deliveries
  4. although the overall frequency of sepsis was stable (P = 0.95), the risk of severe sepsis (p<0.001) and sepsis-related death (p=0.02) increased during the study period
  5. variables associated with the development of severe sepsis included congestive heart failure, chronic liver disease, chronic renal disease, systemic lupus erythematous, and rescue cerclage placement

Full Text: Bauer. Maternal Sepsis Mortality and Morbidity During Hospitalization for Delivery: Temporal Trends and Independent Associations for Severe Sepsis. Anesth Analg 2013;epublished


Critical Care:     Prehospital Cardiac Arrest

Goto and colleagues performed an analysis of a Japanese national database of 209,577 out-of-hospital cardiac arrest patients, investigating whether prehospital adrenaline administration would improve 1-month survival, and found:

  1. more patients had an initial non-shockable rhythm (n=194,085) than shockable rhythm (n=15,492)
  2. in the initial shockable rhythm cohort, not administering adrenaline was associated with improved 
    • prehospital return of spontaneous circulation (27.7% versus 22.8%; p<0.001)
    • 1-month survival (27.0% versus 15.4%; p<0.001)
    • 1-month favorable neurological outcomes (18.6% vs. 7.0%; p<0.001)
  3. in the initial non-shockable rhythm cohort, adrenaline administration was associated with improved
    • prehospital return of spontaneous circulation (18.7% versus 3.0%; p<0.001)
    • 1-month survival (3.9% versus 2.2%; p<0.001)
    • but not an improvement in 1-month favorable neurological outcomes (p=0.62)

Abstract:  Goto. Effects of prehospital epinephrine during out-of-hospital cardiac arrest with initial non-shockable rhythm: An observational cohort study. Critical Care 2013;17:R188


Intensive Care Medicine:     Antimicrobial De-escalation

Garnacho-Montero and colleagues completed a prospective observational study in 712 patients with severe sepsis or septic shock, evaluating 628 due to deaths prior to culture results were avaliable, and examined the effects of antimicrobial discontinuation or narrowing of antimicrobial spectrum after culture results were available, and found:

  1. de-escalation occurred in 219 patients (34.9 %)
  2. using multivariate analysis, factors independently associated with in-hospital mortality were septic shock, SOFA score the day of culture results, and inadequate empirical antimicrobial therapy, whereas de-escalation therapy was a protective factor (odds ratio 0.58; 95 % CI 0.36–0.93)
  3. in 403 patients with adequate empirical therapy de-escalation therapy was a protective factor (OR 0.54; 95 % CI 0.33–0.89) against mortality
  4. de-escalation therapy was a protective factor against 90-day mortality

Abstract:  Garnacho-Montero. De-escalation of empirical therapy is associated with lower mortality in patients with severe sepsis and septic shock. Intensive Care Med 2013;Sep 12th


Critical Care:     Sepsis

Huynh et al undertook a prospective observational cohort study of 1001 patients with severe sepsis, comparing the characteristics and outcomes of culture-negative versus culture-positive bacterial severe sepsis, and found:
  1. there were more culture-positive than culture-negative patients (58.5% versus 41.5%)
  2. gram-negative bacteria were more frequently isolated than gram-positive bacteria (390 versus 257) 
  3. culture-negative patients were more often women, had fewer comorbidities, less physiological derangement and less need for vasoactive agents
  4. culture-negative patients, in comparison with culture-positive patients, had
    • a shorter duration of hospital stay (12 days (7.0-21.0) versus 15.0 (7.0-27.0), P = 0.02)
    • lower ICU mortality
    • lower hospital mortality (35.9% versus 44.0%, P = 0.01),
  5. hospital mortality was lower in the culture-negative group (35.9%), in comparison with
    • the culture-positive subgroup which did not receive early appropriate antibiotics (55.5%, P <0.001) 
    • but not the culture-positive subgroup which did receive early appropriate antibiotics (41.9%, P = 0.11)
  6. after adjusting for covariates, culture positivity was not independently associated with mortality on multivariable analysis

Abstract:  Phua. Characteristics and outcomes of culture-negative versus culture-positive severe sepsis. Critical Care 2013;17:R202


Other observational studies of interest 

Annals of  the American Thoracic Society :   Sepsis

Abstract:  Liu. Fluid Volume, Lactate Values, and Mortality in Sepsis Patients with Intermediate Lactate Values. Annal Am Thor Soc 2013;epublished September 4th


JAMA Internal Medicine:     Futile Therapy

Abstract:  Huynh. The Frequency and Cost of Treatment Perceived to Be Futile in Critical Care. JAMA Intern Med 2013;epublished September 9th  


JAMA Internal Medicine:     Cardiac Arrest Outcome Prediction

Abstract:  Ebell. Development and Validation of the Good Outcome Following Attempted Resuscitation (GO-FAR) Score to Predict Neurologically Intact Survival After In-Hospital Cardiopulmonary Resuscitation. JAMA Intern Med 2013;epublished September 9th  


British Journal of Anaesthesia:     Cardiac Output Monitoring

Abstract:  Bendjelid. Performance of a new pulse contour method for continuous cardiac output monitoring: validation in critically ill patients. Br J Anaesth 2013;111:573-579



Annals of Nutrition & Metabolism


New England Journal of Medicine:     Medicare


Canadian Medical Association Journal:     Tuberculosis


European Journal of Anaesthesiology:     Muscle Relaxants


Lancet:     Research Misconduct


Lancet:     Future Hospital Commission


Review - Clinical


European Journal of Anaesthesiology:     Muscle Relaxants


Indian Journal of Neurosurgery:     Ischaemic Stroke



Annals of Medical and Health Sciences Research:     Peripartum Cardiomyopathy



BioMed Research International:     Spinal Cord Injury


Saudi Journal of Health Science:     COPD



Saudi Journal of Gastroenterology:     Bleeding Peptic Ulcer



Alimentary Pharmacology & Therapeutics:     Autoimmune Hepatitis


Liver International:     Endocannabinoid System


BioMed Research International:     Hepatopulmonary Syndrome



Thrombosis Journal:     New Oral Anti-Coagulants



Journal of Postgraduate Medicine:     Colistin   


Journal of Postgraduate Medicine:     Tuberculosis


PLOS Pathogens:     MERS-CoV


Infection Ecology Epidemiology:     Dengue Virus



Many thanks to Stephan and Gabriel for pointing out two recent errors - in newsletter 90, thinking it was a recent publication, I incorrectly linked to a 2001 community-acquired pneumonia guideline from the American Journal of Respiratory and Critical Care Medicine, while last week I somehow completely miswrote the EchoCRT result findings, which are corrected below. Sincere apologies for these inaccuracies.

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



I hope you find these brief summaries and links useful.

Until next week