Newsletter 104 / December 1st 2013




Welcome to the 104th 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 randomized research studies include investigations into timing of renal replacement therapy initiation, clarithromycin therapy for suspected Gram-negative sepsis, modified N-acetylcysteine protocol for paracetamol overdose, and humidification for noninvasive ventilation. Meta analyses address continuous antibiotic dosing regimes and temporal sepsis mortality changes. Observational studies focus on the prediction of death within 60 minutes following withdrawal of cariopulmonary organ support, temporal changes in the use of the pulmonary artery catheter, renal outcomes after different renal replacement therapy modalities and the attributable mortality risk from early acute kidney injury. There are two new and six updated Cochrane reviews.

This week's guidelines and position statements cover alternatives to allogeneic blood transfusion, safety of parenteral nutrition, vitamin K antagonists and negative pressure therapy for the open abdomen. There is a single editorial on pulmonary hypertension plus several commentaries, including discusssions on traumatic brain injury, the military contribution to trauma care and blood pressure management for acute stroke.

Amongst the clinical review articles are papers on dexmedetomidine, the ongoing controversy regarding brain death, pulmonary artery catheters, pacemakers, ECMO, damage control surgery, nephropathy in the setting of liver disease, surgical site infection, acquired haemophilia A, antimicrobial peptides, sepsis-induced immunosuppression, permissive hypotension and anaphylactic shock. Non-clinical reviews look at models for the analysis of repeated continuous outcome measures, pharmaceutical marketing, and, very relevant at this time of year, a paper on social isolation and loneliness. If you prefer something less clinical, there is a general interest article on biogenesis.

As today is World AIDS Day, it's only fitting to have this as the topic for This Week's Papers, starting with a paper on critical illness in those infected with HIV in tomorrow's Paper of the Day.


Missing Newsletters

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Annual Survey

Today marks two years of consecutive newsletters, the beginning of the end of 2013 and is a good time to get your opinion on how to improve Critical Care Reviews. If you have a minute please complete this very brief anonymous survey. This survey was run last December, with most recommendations either trialled or fully implemented. There are a few that I just haven't got round to yet, but will do. Every comment will be gratefully received, read and considered. Critical Care Reviews is a free, not-for-profit website aiming to aid the busy clinician interface the literature and other relevant online materials.


Critical Care Reviews Meeting

It's just  8 weeks to the 2014 Critical Care Reviews Meeting. This year we discuss the major studies from the past 12 months, hear from our international guest speakers, Prof Alistair Nichol (Dublin/Melbourne), Prof Mervyn Singer (London) and Prof John Marshall (Toronto), and have updates on ICU infections, massive haemorrhage and acute liver failure. The evening session provides an opportunity to chat with our guest speakers in a novel, informal setting - beside a blazing log fire in a beautiful lounge - perfect for a cold winters night. This will be followed by dinner and the chance to meet new colleagues and friends.

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. The Galgorm Resort and Spa is one of Northern Ireland's premier hotels and is a 30 minute drive from Belfast International Airport. Special room rates are available, by quoting the meeting. Please feel free to contact me if you're thinking about making the trip - it would be great to hear from you. Now is a good time to register before such thoughts are rightly forgotten during the approaching festivities.

This year, the meeting will be run in association with the Northern Ireland Intensive Care Society. Further details, the meeting programme, and registration can be accessed via these links.



Randomized Controlled Trials

American Journal of Kidney Diseases:     Renal Replacement Therapy for AKI

Jamale and colleagues completed a prospective, open label, 2-arm, randomized, controlled trial, in 208 Indian patients with acute kidney injury, comparing earlier-start dialysis (serum urea nitrogen and/or creatinine levels increased to 70 and 7 mg/dL, respectively; n=102), with usual-start dialysis commenced when clinically indicated as judged by treating nephrologists (n=106), and found:

  1. baseline characteristics were similar between groups
  2. dialysis rates were
    • intervention group: 91.1% 
    • control group:  83.1%
  3. mean serum urea nitrogen and serum creatinine levels at dialysis therapy initiation were
    • intervention group: 
      • serum urea nitrogen 71.7 ± 21.7 mg/dL (SD)
      • serum creatinine 7.4 ± 5.3 mg/dL
    • control group:
      • serum urea nitrogen 100.9 ± 32.6 mg/dL
      • serum creatinine 10.41 ± 3.3 mg/dL 
  4. there were no significant between group differences in
    • in-hospital mortality
      • intervention group: 20.5%
      • control group: 12.2%
      • relative risk 1.67; 95% CI 0.88 to 3.17 (P  = 0.2)
    • dialysis dependency at 3 months
      • intervention group: 4.9%
      • control group: 4.7%
      • relative risk 1.04; 95% CI 0.29 to 3.7 (P = 0.9)

Abstract:  Jamale. Earlier-Start Versus Usual-Start Dialysis in Patients With Community-Acquired Acute Kidney Injury: A Randomized Controlled Trial. American Journal of Kidney Diseases 2013;62(6):1116-1121


Journal of Antimicrobial Chemotherapy:     Clarithromycin

Giamarellos-Bourboulis and colleagues completed a multicentre, randomized, double-blind, placebo-controlled trial in 600 patients with suspected Gram-negative sepsis, evaluating the addition of clarithromycin (1g IV once daily for 4 days) to standard therapy, and found:

  1. similar group baseline characteristics
  2. no difference in
    • 28 day mortality (P=0.671)
      • placebo group: 17.1% (51 deaths) 
      • clarithromycin 18.5% (56 deaths)
    • median time until resolution of infection 
      • placebo group: 5 days
      • clarithromycin group: 5 days
    • serious adverse events (P = 0.502)
      • placebo group: 1.3%
      • clarithromycin 0.7%
  3. in the cohort with septic shock and multiple organ dysfunctions, clarithromycin therapy was associated with reduced
    • mortality  (P=0.020)
      • placebo group:  73.1% (19 of 26 patients) 
      • clarithromycin group:  53.6% (15 of 28 patients) 
    • quicker resolution of sepsis  (P = 0.037)
      • placebo group:  10 days
      • clarithromycin group:  6 days
  4. clarithromycin therapy was associated with reduced cost of hospitalization (P = 0.044)

Abstract:  Giamarellos-Bourboulis. Effect of clarithromycin in patients with suspected Gram-negative sepsis: results of a randomized controlled trial. J Antimicrob Chemother 2013;epublished November 28th   


The Lancet:    Paracetamol Poisoning

Bateman and colleagues completed a three centre, double-blind, randomised factorial study in 222 patients (217 assessed) with acute paracetamol overdose, and compared a standard intravenous acetylcysteine regimen (duration 20·25 h) or a shorter (12 h) modified protocol, with or without intravenous ondansetron pretreatment (4 mg), and found:

  1. at 2 hours, there was a reduced incidence of side effects (vomiting, retching, or need for rescue antiemetic treatment) with  
    • the shorter, modified protocol
      • modified protocol: 39 of 108 patients 
      • standard protocol:  71 of 109 patients
      • adjusted odds ratio 0·26, 97·5% CI 0·13—0·52; p<0·0001
    • ondansetron pretreatment
      • ondansetron: 45 of 109 patients
      • placebo: 65 of 108 patients
      • adjusted odds ratio 0·41, 0·20—0·80; p=0·003
  2. the modified protocol was associated with a reduced incidence of severe anaphylactoid reactions
    • modified protocol:  5 patients 
    • standard protocol:  31 patients
    • adjusted common odds ratio 0·23, 97·5% CI 0·12—0·43; p<0·0001
  3. for patients with a 50% increase in alanine aminotransferase activity
    • there was no difference between standard and modified protocols
      • standard protocol:  9 of 110 patients
      • modified protocol:  13 of 112 patients
      • adjusted odds ratio 0·60, 97·5% CI 0·20—1·83
    • an increase with ondansetron pretreatment
      • ondansetron: 16 of 111 patients 
      • placebo: 6 of 111 patients 
      • adjusted odds ratio 3·30, 97·5% CI 1·01—10·72; p=0·024

Abstract:  Bateman. Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomised controlled trial. Lancet 2013;epublished November 28th


Intensive Care Medicine:     Noninvasive Ventilation Humidification

Lellouche et al undertook a multicenter, stratified, randomized controlled study in 247 patients with respiratory failure receiving non-invasive ventilation via an ICU ventilator, comparing the use of heated humdifiers (n=119) with heat and moisture exchangers filters (n=128), and found:

  1. groups were comparable at baseline
  2. no significant difference in
    • intubation rates (P=0.28)
      • HMEF: 29.7 %
      • HH: 36.9 %
    • PaCO2, even in the subgroup of hypercapnic patients.
    • NIV duration
    • length of stay
      • ICU
      • hospital
    • ICU mortality (P=0.18)
      • HMEF: 14.1%
      • HH:  21.5 %

AbstractLellouche. Impact of the humidification device on intubation rate during noninvasive ventilation with ICU ventilators: results of a multicenter randomized controlled trial. Intensive Care Med 2013;epublished November


Meta Analysis

Critical Care:     Antibiotic Dosing

Chant et al pooled data from 13 randomized controlled trials (n=782) and 13 cohort studies (n=2,117), examining whether extended/continuous infusions of antimicrobials were superior to traditional dosing methods in critically ill patients, and found:

  1. based on RCT data
    • continuous/extended infusions significantly reduced
      • clinical failure rates
        • relative risk  0.68, 95% CI 0.49 to 0.94, P = 0.02
      • intensive care unit length of stay
        • mean difference -1.5 days, 95% CI -2.8 to -0.2 days, P = 0.02
    • there was no difference in mortality
      • RR 0.87, 95% CI 0.64 to 1.19, P = 0.38
    • no significant between-trial heterogeneity for these analyses (I2 = 0%)
  2. based on combined pooled RCT and cohort study data
    • there was a trend toward reduced mortality with continuous/extended infusions
    • RR 0.83, 95% CI 0.69 to 1.00, P = 0.054

Full Text:  Chant. Optimal dosing of antibiotics in critically ill patients using continuous/extended infusions: a systematic review and meta-analysis. Critical Care 2013;17:R279


Critical Care Medicine:     Temporal Sepsis Mortality

Stevenson et al evaluted 36 multicenter randomized trials from 1991 to 2009 (n=14,418 control patients), producing standardized mortality ratios for each trial from observed 28-day mortality of usual care patients and predicted mortality from severity-of-illness scores, as well as comparing trial mortality with administrative data from the Nationwide Inpatient Sample (1993 to 2009), and found:

  1. severe sepsis patients receiving usual care had a 28-day mortality of 33.2%
  2. trial mortality decreased 3.0% annually (95% CI 0.8% to 5.0%; p = 0.009)
    • 1991-1995:  46.9% (standardized mortality ratio 0.94; 95% CI 0.86 to 1.03)
    • 2006-2009:  29% (standardized mortality ratio 0.53; 95% CI 0.50 to 0.57) 
  3. trends in hospital mortality among patients with severe sepsis identified from administrative data were similar to trends identified from clinical trials
    • Angus definition: 4.7% annual change; 95% CI 4.1% to 5.3%; p = 0.69
    • Martin definition: 3.5% annual change; 95% CI 3.0% to 4.1%; p = 0.97

Abstract:  Stevenson. Two Decades of Mortality Trends Among Patients With Severe Sepsis: A Comparative Meta-Analysis. Crit Care Med 2013;epublished November 6th


Observational Studies

Critical Care Medicine:     Prediction of Death

Brieva and colleagues completed a multicentre, prospective, longitudinal cohort study of 765 consecutive adult patients having withdrawal of cardiorespiratory support in Australia, using a random split-half method to make two independent samples for development and testing predictive indices, and found:
  1. 49.3% of patients died within 60 minutes of withdrawal of cardiorespiratory support
  2. ICU specialist opinion was the best individual predictor of death
    • unadjusted odds ratio 15.42 (95% CI 9.33 to 25.49) 
    • adjusted odds ratio 8.44 (95% CI 4.30 to 16.58).
  3. for a predictive index incorporating the ICU specialist opinion and clinical variables
    • development set
      • AUC 0.89 (95% CI 0.86 to 0.92) 
    • test set
      • AUC 0.84 (95% CI 0.80 to 0.88) 
  4. for a second index using only clinical variables
    • development set
      • AUC 0.86 (95% CI 0.82 to 0.89)
    • test set
      • AUC 0.78 (95% CI 0.73 to 0.83)
  5. the ICU specialist prediction of death within 60 minutes was independently associated with 
    • pH
    • Glasgow Coma Scale
    • spontaneous respiratory rate
    • positive end-expiratory pressure
    • systolic blood pressure

Abstarct:  Brieva. Prediction of Death in Less Than 60 Minutes Following Withdrawal of Cardiorespiratory Support in ICUs. Crit Care Med 2013;41(12):2677-2687


Critical Care Medicine:     Pulmonary Artery Catheterization

Gershengorn and colleagues performed a multicentre, prospective, observational study assessing trends in pulmonary artery catheter use in the USA from 2001 to 2008, and found:

  1. total pulmonary artery catheter use decreased over time (P < 0.001)
    • 2001–2003:  10.8% 
    • 2006–2008:  6.2%
  2. insertion of pulmonary artery catheters in ICU decreased over time (P < 0.001)
    • 2001–2003: 4.2% 
    • 2006–2008: 2.2% 
  3. In the 2006–2008 cohort, comparing ICUs in the top quartile versus bottom quartile for in-ICU pulmonary artery catheter insertion (3.4–25.0% of patients), factors asociated with PAC use were
    • surgical ICUs (54.2% vs 21.7%) (P = 0.070)
    • teaching hospitals (54.2% vs 4.3%) (P = 0.001)
    • surgeon leadership (40.9% vs 13.0%) (P = 0.067)
  4. using multivariable regression, ICU patients more likely to have pulmonary artery catheters were
    • surgical patients (P < 0.001) 
    • all patients in surgical ICUs (P = 0.057)

Critical Care Medicine:     Acute Kidney Injury

Vaara et al performed a secondary analysis of the Finnish Acute Kidney Injury study, matching 477 patients with acute kidney injury on ICU days 1 to 5 with 477 patients who did not develop acute kidney injury during this period, aiming to estimate the excess mortality attributable to acute kidney injury, and found:

  1. 90-day mortality was
    1. AKI: 26.2% 
    2. non-AKI: 17.6%
  2. absolute excess 90-day mortality attributable to acute kidney injury was estimated at 8.6% (95% CI 2.6-17.6%)
  3. population attributable 90-day mortality risk associated with acute kidney injury was 19.6% ( 95% CI 10.3-34.1%)

Abstract:  Vaara. The Attributable Mortality of Acute Kidney Injury: A Sequentially Matched Analysis.  Crit Care Med 2013;epublished November 6th


Critical Care Medicine:     Renal Replacement Therapy

Wald et al undertook a retrospective Canadian database analysis comparing, in a 1:1 matched fashion, the long term renal outcomes of patients with acute kidney injury treated with either continuous renal replacement therapy (n=2,004) or intermittent haemodialysis (n=2,004), and found:

  1. a lower risk of chronic dialysis in patients initially treated with continuous renal replacement therapy
    • hazard ratio 0.75 (95% CI 0.65 to 0.87)
  2. this risk reduction was more pronounced in patients with 
    • preexisting chronic kidney disease (p value for interaction term = 0.065) 
    • heart failure (p value for interaction term = 0.035)

Abstract:  Wald. The Association Between Renal Replacement Therapy Modality and Long-Term Outcomes Among Critically Ill Adults With Acute Kidney Injury: A Retrospective Cohort Study. Crit Care Med 2013;epublished November 22nd


Other Studies of Interest





Cochrane Reviews








European Respiratory Review:     Pulmonary Arterial Hypertension  




Review - Clinical




















Critical Care Nurse:     Permissive Hypotension




Review - Basic Science


Review - Non-Clinical


General Interest

Research and Reports in Biology:     Biogenesis



I hope you find these brief summaries and links useful.

Until next week