Newsletter 121 / March 30th 2014




Welcome to the 121st 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 bacterial meningitis, heart failure, peptic ulcer bleeding and intelligent volume-assured pressure support; meta analyses address oral chlorhexidine therapy, stem cell therapy in acute myocardial infarction and timing of tracheostomy; observational studies focus on ARDS studies, traumatic hypofibrinogenaemia and balanced crystalloid therapy in sepsis, while additional studies investigate antimicrobial therapy in intra-abdominal sepsis, predictors of mortality among bacteremic patients with septic shock receiving appropriate antimicrobial therapy, optimal cerebral perfusion pressure in intracranial haemorrhage and trauma deaths in the USA.

There are a number of guidelines this week, including the development of a new international guideline for the determination of death, as well as guidance on atrial fibrillation and end-of-life care in stroke. Editorials address multidisciplinarity in emergency and critical care medicine, continuous renal replacement therapy, stroke volume optimisation, and regenerative heart failure therapy. Commentaries focus on nutritional support, tranexamic acid and statins for delirium.  Amongst the clinical review articles are papers on severe traumatic brain injury, neurocritical care myths, ventilator-associated pneumonia, thoracic surgery analgesia, drug-induced liver injury, cirrhosis-associated kidney injury, infectious complications of blood transfusion, multi-drug resistant gram negative infections, damage control surgery, an overview of medical devices, latex glove allergy plus several articles on therapuetic hypothermia.

The topic for This Week's Papers is the physiology of venous return and cardiac output, starting with a classic paper from Guyton from almost 50 years ago, in tomorrow's Paper of the Day.

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Randomized Controlled Trials

Glimåker and colleagues performed a prospective intervention-control study, comparing early intracranial pressure-targeted treatment (n=52) with standard intensive care management (n=53), in 105 critically ill, mechanically ventilated adults with community-acquired acute bacterial meningitis. ICP targeted therapies included cerebrospinal fluid drainage using external ventricular catheters (n = 48), osmotherapy (n = 21), hyperventilation (n = 13), external cooling (n = 9), gram-doses of methylprednisolone (n = 3) and deep barbiturate sedation (n = 2), aiming at ICP <20 mmHg and a cerebral perfusion pressure of >50 mmHg. The authors found:

ICP guided therapy was associated with

  1. a lower mortality at 2 months
    • 10% versus 30%; relative risk reduction 68%; p<0.05
  2. improved recovery (Glasgow outcome score and hearing)
    • 54% versus 32%;  relative risk reduction 40%; p<0.05

Full Text:  Glimåker. Neuro-Intensive Treatment Targeting Intracranial Hypertension Improves Outcome in Severe Bacterial Meningitis: An Intervention-Control Study. PLoS ONE 2014;9(3):e91976

Nalos and colleagues completed a prospective, randomized, controlled, open label, pilot clinical trial in 40 patients with acute heart failure comparing an intervention of 3 ml/kg bolus over 15 min of half-molar sodium lactate followed by 1 ml/kg/h continuous infusion for 24 h, with a control of 3 ml/kg bolus of Hartman's solution without continuous infusion, and found:

  1. infusion of half-molar sodium lactate
    • increased
      • cardiac output from 4.05 +/- 1.37 L/min to 5.49 +/- 1.9 L/min, (P < 0.01)
      • TAPSE from 14.7 +/- 5.5 mm to 18.3 +/- 7 mm (P = 0.02)
      • plasma
        • sodium (136 +/- 4 to 146 +/- 6, P<0.01)
        • pH increased (7.40 +/- 0.06 to 7.53 +/- 0.03, P<0.01)
    • decreased
      • plasma
        • potassium, chloride and phosphate levels
  2. no significant differences in
    • need for
      • vasoactive therapy
      • respiratory support
    • renal or liver function tests
    • duration of stay
      • ICU 
      • hospital 
    • mortality
      • 28 day
      • 90 day

Full Text:  Nalos. Half-molar sodium lactate infusion improves cardiac performance in acute heart failure: a pilot randomized controlled clinical trial. Critical Care 2014;18:R48

Cheng and colleagues undertook a randomized controlled trial in 293 patients with peptic ulcer bleeding who had achieved endoscopic haemostasis followed by a three day esomeprazole infusion, comparing three groups:

  • patients with a Rockall score ≥6
    1. oral esomeprazole 40 mg twice daily for a subsequent 11 days, followed by once daily to day 28 (n=93)
    2. oral esomeprazole 40 mg once daily to day 28 (n=94)
  • patients with a Rockall score <6
    1. oral esomeprazole 40 mg once daily to day 28 (n=89)

and found:

  1. among patients with Rockall scores ≥6, oral twice daily versus once daily PPI administration was associated with:
    • a higher cumulative rebleeding-free proportion (p=0.02, log-rank test).
    • a lower rebleeding rate  (4th–28th day: 10.8% vs 28.7%, p=0.002)
  2. comparing the twice daily regimen in patients with Rockall scores ≥6 with the group with a Rockall score <6, the twice daily PPI regimen was associated with
    • a lower proportion of patients free from recurrent bleeding during the 4th–28th day (p=0.03, log-rank test)

Abstract:  Cheng. Double oral esomeprazole after a 3-day intravenous esomeprazole infusion reduces recurrent peptic ulcer bleeding in high-risk patients: a randomised controlled study. Gut 2014;epublished March 21st

Kelly and colleagues completed a randomized crossover trial, examining whether intelligent volume-assured pressure support (iVAPS, a hybrid mode of servoventilation, providing constant automatic adjustment of pressure support (PS) to achieve a target ventilation determined by the patient's requirements) was non-inferior to standard PS ventilation, for controlling nocturnal hypoventilation in 18 patients with nocturnal hypoventilation and naive to NIV, and found:

  1. iVAPS delivered a lower median PS compared with standard PS (8.3(5.6–10.4) vs 10.0(9.0–11.4) cmH2O; P = 0.001) for the same ventilatory outcome (mean overnight: SpO2 96(95–98) vs 96(93–97)%; P = 0.13 and PtcCO2 6.5(5.8–6.8) vs 6.2(5.8–6.9); P  = 0.54)
  2. no difference in outcome between ventilator modes for spirometry, respiratory muscle strength, sleep quality, arousals or O2 desaturation index
  3. greater adherence with iVAPS (5:40(4:42–6:49) vs 4:20(2:27–6:17) hh:mm/night; P = 0.004)

Abstract:  Kelly. Randomized trial of ‘intelligent’ autotitrating ventilation versus standard pressure support non-invasive ventilation: Impact on adherence and physiological outcomes. Respirology 2014;epublished March 24th

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Meta Analyses

Klompas et al pooled data from 16 randomized controlled trials (n=3,630) comparing oral chlorhexidine vs placebo in adults receiving mechanical ventilation, and found:

chlorhexidine therapy was associated with

    1. for lower respiratory tract infections/pneumonia
      • lower incidence of lower respiratory tract infections in cardiac surgery patients  (relative risk 0.56; 95% CI 0.41 to 0.77)
      • no significant difference in VAP risk in double-blind studies of non–cardiac surgery patients (RR 0.88; 95% CI 0.66 to 1.16)
    2. no significant mortality difference
      • in cardiac surgery studies (RR 0.88, 95% CI 0.25 to 2.14)
      • nonsignificantly increased mortality in non–cardiac surgery studies (RR 1.13; 95% CI 0.99 to 1.29)
    3. no significant differences in mean duration of mechanical ventilation or intensive care length of stay

Abstract:  Klompas. Reappraisal of Routine Oral Care With Chlorhexidine Gluconate for Patients Receiving Mechanical Ventilation: Systematic Review and Meta-Analysis. JAMA Intern Med 2014;epublished March 24th  

De Jong et al reviewed data from 22 randomized controlled trials examining the efficacy of bone marrow–derived mononuclear cell therapy in patients with acute myocardial infarction, and found:

bone marrow–derived mononuclear cell therapy was associated with:

    1. increased left vetricular ejection fraction  (+2.10%; 95% CI 0.68 to 3.52; p=0.004) (seems like an error with either the CI or p value)
    2. preservation of LV end-systolic volume (−4.05 mL; 95% CI −6.91 to −1.18; p=0.006) 
    3. reduction in infarct size (−2.69%; 95% CI −4.83 to −0.56; p=0.01)
    4. using MRI-derived end points (9 RCTs), there was no effect on cardiac function, volumes, or infarct size
    5. no beneficial effect on major adverse cardiac and cerebrovascular event rates after a median follow-up duration of 6 months

Abstract:  de Jong. Intracoronary Stem Cell Infusion After Acute Myocardial Infarction: A Meta-Analysis and Update on Clinical Trials. Circ Cardiovasc Interv 2014;epublished March 25th

Huang et al pooled data from 9 randomized clinical trials (n=2,072), comparing (1) early tracheostomy within 10 days after initiation of laryngeal intubation, (2) late tracheostomy after 10 days of laryngeal intubation AND (3) prolonged intubation for critically ill patients receiving long-term ventilation, and found:

early tracheostomy, compared with late tracheostomy or prolonged intubation, did not significantly reduce

  1. short-term mortality (relative risk  0.91; 95% CI 0.81 to 1.03; p=0.14)
  2. long-term mortality (RR 0.90; 95% CI 0.76 to 1.08; p=0.27)
  3. length of ICU stay (weighted mean difference (WMD) −4.41 days; 95% CI −13.44 to 4.63 days; p=0.34)
  4. ventilator-associated pneumonia incidence (RR 0.88; 95% CI 0.71 to 1.10; p=0.27) 
  5. duration of mechanical ventilation (WMD − 2.91 days; 95% CI = −7.21 to 1.40 days; p=0.19)

Full Text:  Huang. Timing of tracheostomy in critically ill patients: a meta-analysis. PLoS One. 2014 Mar 25;9(3):e92981

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Observational Studies

Tonelli and colleagues examined all published randomized controlled trials (n=159) in ARDS that reported on mortality, and of respective meta-analyses (n=29), and found:

  1. of 159 published RCTs 
    • 93 had overall mortality reported (n=20,671)
    • 44 trials (n=14,426) reported mortality as a primary outcome
  2. regarding statistically significant effects
    1. a survival benefit was observed in eight trials (seven interventions) 
    2. a reduced survival was reported in two trials 
  3. in RCTs with more than 50 deaths in at least one treatment arm (n=21)
    • two showed a statistically significant mortality benefit of the intervention (lower tidal volumes and prone positioning)
    • one showed a statistically significant mortality benefit only in adjusted analyses (cisatracurium)
    • one showed a significant worsening of mortality (high-frequency oscillatory ventilation)
  4. across 29 meta-analyses
    • the most consistent evidence was seen for low tidal volumes and prone positioning in severe ARDS

Abstract:  Tonelli. Effects of interventions on survival in acute respiratory distress syndrome: an umbrella review of 159 published randomized trials and 29 meta-analyses. Intensive Care Med 2014;epublished March 26th

Hagemo and colleagues performed a four-centre observational study evaluating the prevalence and relationships of hypofibrinogenaemia in severe trauma (n=1,133), and found:

  1. the fibrinogen concentration was
    • <2 g/L in 19.2%
    • ≤1.5g/L in 8.2%
  2. a non-linear relationship between fibrinogen concentration and mortality
    • a breakpoint for optimal fibrinogen concentration was 2.29 g/L (95% CI 1.93 to 2.64)
    • below 2.29 g/L the odds of death by 28 days was reduced by a factor of 0.08 (95% CI 0.03 to 0.20) for every unit increase in fibrinogen concentration
  3. unique contributors to low fibrinogen concentrations on arrival were:
    • younger age
    • male gender
    • lengthened time from injury
    • low base excess
    • high injury severity score

Full Text:  Hagemo. Prevalence, predictors and outcome of hypofibrinogenaemia in trauma: a multicentre observational study. Critical Care 2014;18:R52

Raghunathan et al performed a retrospective, propensity matched study of 53,448 patients with sepsis, including 3,396 (6.4%) that received balanced fluids, comparing outcomes after resuscitation with balanced versus with non-balanced crystalloid fluids, and found:

  1. patients treated with balanced fluids were
    • younger 
    • less likely to have
      • heart failure
      • chronic renal failure
    • more likely to receive
      • mechanical ventilation
      • invasive monitoring
      • colloids
      • steroids
      • larger crystalloid volumes (median 7 vs 5 L)
  2. among 6,730 patients in a propensity-matched cohort, receipt of balanced fluids was associated with
    • lower in-hospital mortality (19.6% vs 22.8%; relative risk 0.86; 95% CI 0.78 to 0.94)
    • lower mortality, which was progressively lower among patients receiving larger proportions of balanced fluids
  3. no significant differences in the prevalence of
    • acute renal failure (with and without dialysis) 
    • lengths of stay
      • in-hospital
      • ICU

Abstract:  Raghunathan. Association Between the Choice of IV Crystalloid and In-Hospital Mortality Among Critically Ill Adults With Sepsis. Crit Care Med 2014;epublished March 26th

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Additional Studies

Randomized Controlled Trials

Observational Studies

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I hope you find these brief summaries and links useful.

Until next week