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Critical Care Reviews Newsletter

March 24th 2013



Welcome to the 68th 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 has seen a plethora of interesting research studies published across NEJM, JAMA, AJRCCM and other journals. In addition to these high powered primary randomized controlled trials, there are secondary analyses from SAFE and EDEN. There are two reports from the Brussels meeting, including an update from the Italian ALBIOS study, partly presented at Lisbon last October.

This week's guidelines cover acute kidney injury, thallium poisoning and surgical antimicrobial prophylaxis.

Amongst the clinical review articles are two superb series from Critical Care. The first, "A selective look back and a glimpse forward" has just been featured as our topic of the week. The second, the "Annual Update in Intensive Care and Emergency Medicine 2013" features 10 reviews from this yearly update book which accompanies the Brussels meeting. As well as these series, there are neurological, respiratory, sepsis and circulatory review articles, including a great set of papers on embolic conditions from the International Journal of Critical Illness and Injury Science. There are also a couple of review articles on anaesthetic related topics - safety in anaesthesia and the postanaethetic unit.

The topic for This Week's Papers is the latest series from Critical Care, starting with a paper on recent advances in assessing volume responsiveness in mechanically ventilated patients in tomorrow's Paper of the Day.



American Journal of Respiratory and Critical Care Medicine:     Activated Protein C

Annane and colleagues performed a multi-centre placebo-controlled, double-blind, 2x2 factorial design trial in 411 patients with persistent septic shock. Patients were randomly assigned to activated protein C alone, hydrocortisone and fludrocortisone alone, their respective combinations or their respective placebos. The trial was suspended in October 2011, after the worldwide withdrawal of activated protein C following the PROWESS Shock study (APC: n=208 and placebo: n=203). There was no significant interaction between APC  and low-dose steroids (P=0.47). There was no difference in 90 day mortality (APC: 47.6% versus placebo: 46.3%; P=0.79). Similarly, there was no difference in any secondary outcomes or serious adverse events. Conclusion: In adults with persistent severe septic shock, APC was neither efficacous nor harmful.

Abstract:  Annane. Recombinant Human Activated Protein C for Adults with Septic Shock: a Randomized Controlled Trial (APROCCHSS Trial). Am J Respir Crit Care Med 2013; epublished March 22nd


American Journal of Respiratory and Critical Care Medicine:     Research Recruitment

Burns et al completed a prospective, observational study of all critically ill adults eligible to participate in research studies at 23 Canadian ICUs. 8.9% of eligible patients made decisions for themselves. In 453 eligibility events, consent was not required in 14 (3.1%), missed in 131 (28.9%), infeasible due to operational reasons in 129 (28.5%), obtained in 140 (30.9%) and declined in 39 (8.6%). Over half (57%) of all opportunities to recruit patients were missed or infeasible largely due to research team workload, limited availability, narrow time windows for inclusion, difficulties in contacting families, non-existent substitute decision makers (SDMs), physician refusals and protocols prohibiting co-enrollment. The rationale for providing consent differed between patients and SDMs. Greater research coordinator experience and site research volume were significant predictors of fewer declined consents. Conclusion: Recruitment for research is problematic, with approximately 60% of possible opportunities missed; especially considering less than 10% of approaches for consent are declined.

Abstract:  Burns. Research Recruitment Practices of Critically Ill Patients: A Multicenter, Cross-Sectional Study (The Consent Study). Am J Respir Crit Care Med 2013; epublished March 22nd


American Journal of Respiratory and Critical Care Medicine:     Weaning

Burns and colleagues undertook a pilot randomized trial comparing automated weaning (n=49) with protocolized weaning (n=43) in critically ill adults who tolerated at least 30 minutes of pressure support and either failed or were not yet ready to undergo a spontaneous breathing trial. Both groups utilized pressure support and spontaneous breathing trials, used a common PEEP/FiO2 chart, sedation protocol and criteria for extubation, reintubation and noninvasive ventilation. Patients treated with automated weaning had significantly shorter median times to first successful breathing trial (1.0 vs. 4.0 d, p<0.0001), extubation (3.0 vs. 4.0 d, p=0.02), successful extubation (4.0 vs. 5.0 d, p=0.01) and underwent fewer tracheostomies and episodes of protracted ventilation. Conclusion: In a small pilot study, automated weaning was superior to protocolized weaning with regard to ventilation outcomes.

Abstract:  Burns. Wean Earlier and Automatically with New Technology (The WEAN Study): A Multicentre, Pilot Randomized Controlled Trial. Am J Respir Crit Care Med 2013; epublished March 22nd


Annals of the American Thoracic Society:     Noninvasive Ventilation

Walkey et al identified 11,659,668 cases of acute respiratory failure from the American Nationwide Inpatient Sample during years 2000 to 2009 and evaluated NIV utilization trends and failure rates.The proportion of patients with COPD who received NIV increased from 3.5% in 2000 to 12.3% in 2009 (250% increase), and the proportion of patients without COPD who received NIV increased from 1.2% in 2000 to 6.0% in 2009 (400% increase). The rate of increase in the use of NIV was significantly greater for patients without COPD (18.1% annual change) than for patients with COPD (14.3% annual change; P = 0.02). Patients without COPD were more likely to have failure of NIV requiring endotracheal intubation (adjusted odds ratio, 1.19; 95% CI 1.15–1.22; P < 0.0001). Patients in whom NIV failed had higher hospital mortality than patients receiving mechanical ventilation without a preceding trial of NIV (adjusted odds ratio, 1.14; 95% CI 1.11–1.17; P < 0.0001). Conclusion: NIV usage has increased at a similar rate for all causes of respiratory failure, but is more likely to fail in patients without COPD, with NIV failure being associated with increased mortality.

Abstract:  Walkey. Use of Noninvasive Ventilation in Patients with Acute Respiratory Failure, 2000-2009: A Population-Based Study. Ann Am Thorac Soc 2013;10(1):10-17


British Medical Journal:     Feeding in ALI

Needham and colleagues completed a prospective longitudinal follow-up evaluation of the randomized EDEN trial, to evaluate, for up to six days, the effect of initial low energy permissive underfeeding (“trophic feeding”) versus full energy enteral feeding (“full feeding”) on physical function and secondary outcomes in 525 patients with acute lung injury. Survivors had substantial physical, psychological, and cognitive impairments, reduced quality of life, and impaired return to work. Initial trophic versus full feeding did not affect mean SF-36 physical function at 12 months (55 (SD 33) v 55 (31), P=0.54), survival to 12 months (65% v 63%, P=0.63), or nearly all of the secondary outcomes. Conclusion: In survivors of acute lung injury, there was no difference in physical function, survival, or multiple secondary outcomes at 6 and 12 month follow-up after initial trophic or full enteral feeding.

Full TextNeedham. One year outcomes in patients with acute lung injury randomised to initial trophic or full enteral feeding: prospective follow-up of EDEN randomised trial. BMJ 2013;346:f1532


Journal of Neurotrauma:     Thromboprophylaxis in Traumatic Brain Injury

Aimun completed a systematic review and meta analysis (5 retrospective studies, n=1624) to assess the safety and efficacy of pharmacological prophylaxis within 72 h of traumatic brain injury. Pharmacological prophylaxis was dichotomized to early (n=713) or late (n=911) at 72 h post-injury. There were less venothromboembolic events in the early group (43 versus 106; risk ratio 0.52; 95% CI: 0.37 - 0.73), without an increase in the relative risk of intracranial hemorrhage progression 0.64 (95% CI: 0.35 - 1.14). Conclusion: In a systematic review and meta analysis of 5 retrospective studies, early pharmacological prophylaxis reduced the risk of venothromboembolism without affecting progression of intracranial hemorrhage.

Abstract:  Aimun. Safety and Efficacy of Early Pharmacological Thromboprophylaxis in Traumatic Brain Injury: Systematic Review and Meta-Analysis. J Neurotrauma 2013; epublished March 21st


Journal of Neurotrauma:     Albumin in Traumatic Brain Injury

Cooper and colleagues performed a secondary analysis of the SAFE study, investigating 321 patients with traumatic brain injury who underwent intracranial pressure monitoring. There was a significant linear increase in mean ICP (1.30±0.33 vs. −0.37±0.36, p=0.0006) and significantly more deaths (34.4% vs. 17.4%; p=0.006) in the albumin group (n=164) compared with saline (n=157) when ICP monitoring was discontinued during the first week; but not when monitoring ceased during the second week (−0.08±0.44 vs. −0.23±0.38, p=0.79; and 18.6% vs. 12.1%; p=0.36 respectively). There were statistically significant differences in the mean total daily doses of morphine (−0.42±0.07 vs. −0.66±0.0, p=0.0009), propofol (−0.45±0.11 vs. −0.76±0.11; p=0.034) and noradrenaline (−0.50±0.07 vs. −0.74±0.07) and in temperature (0.03±0.03 vs. 0.16±0.03; p=0.0014) between the albumin and saline groups when ICP monitoring ceased during the first week. Conclusion: The most likely cause of increased mortality associated with albumin use in traumatic brain injury is an increase in intracranial pressure.

Abstract:  Cooper. Albumin Resuscitation for Traumatic Brain Injury: Is Intracranial Hypertension the Cause of Increased Mortality? J Neurotrauma 2013; epublished March 21st


Surgical Infections:     Tracheostomy

Park et al undertook an 8 year prospective single-institution study in 640 ICU patients to compare the incidence of surgical site infection (SSI) after open versus percutaneous tracheostomy and to discern whether there were any differences in outcome.The majority of patients were male (56.1%) and white (62.5%) with a mean age of 43.2±20.2 years, ISS of 30.7±13.2 points, and APACHE score of 13.3±6.3 points. The majority of patients were admitted for blunt trauma (85.1%). A total of 330 open and 310 percutaneous tracheostomies were performed, with 36 SSIs (5.3%) occuring. There was a lower rate of SSIs with percutaneous tracheostomy (3.4% versus 7%; p=0.04). There was no difference in hospital or ICU lengths of stay, or duration of mechanical ventilation. Conclusion: The risk of SSI is significantly lower after percutaneous than open tracheostomy.

Full Text:  Park. Percutaneous versus Open Tracheostomy: Comparison of Procedures and Surgical Site Infections. Surgical Infections. February 2013, 14(1): 21-23


New England Journal of Medicine:     Cortisol Metabolism

Boonen and colleagues completed an observation study in 158 critically ill patients and 64 matched controls, testing five aspects of cortisol metabolism: (1) daily levels of corticotropin and cortisol; (2) plasma cortisol clearance, metabolism, and production during infusion of deuterium-labeled steroid hormones as tracers; (3) plasma clearance of 100 mg of hydrocortisone; (4) levels of urinary cortisol metabolites; and (5) levels of messenger RNA and protein in liver and adipose tissue, to assess major cortisol-metabolizing enzymes. Total and free circulating cortisol levels were consistently higher in the patients than in controls, whereas corticotropin levels were lower (P<0.001 for both comparisons). Cortisol production was 83% higher in the patients (P=0.02). There was a reduction of more than 50% in cortisol clearance during tracer infusion and after the administration of 100 mg of hydrocortisone in the patients (P≤0.03 for both comparisons). All these factors accounted for an increase by a factor of 3.5 in plasma cortisol levels in the patients, as compared with controls (P<0.001). Impaired cortisol clearance also correlated with a lower cortisol response to corticotropin stimulation. Reduced cortisol metabolism was associated with reduced inactivation of cortisol in the liver and kidney, as suggested by urinary steroid ratios, tracer kinetics, and assessment of liver-biopsy samples (P≤0.004 for all comparisons).  Conclusion: During critical illness, reduced cortisol breakdown, related to suppressed expression and activity of cortisol-metabolizing enzymes, contributed to hypercortisolemia and hence corticotropin suppression.

Full Text:  Boonen. Reduced Cortisol Metabolism during Critical Illness. N Eng J Med 2013; epublished March 19th


Journal of the American Medical Association:     Severe Sepsis

Opal and colleagues performed a randomized, double-blind, placebo-controlled, multinational phase 3 trial investigating whether eritoran, a TLR4 antagonist which blocks lipopolysaccharide-TLR4 binding, would significantly reduce sepsis-induced mortality. Patients with severe sepsis (n = 1961) were randomized and treated within 12 hours of onset of first organ dysfunction in a 2:1 ratio with a 6-day course of either eritoran tetrasodium (105 mg total) or placebo. Baseline characteristics of the 2 study groups were similar. In the modified intent-to-treat analysis (randomized patients who received at least 1 dose) there was no significant difference in the primary end point of 28-day all-cause mortality with 28.1% (366/1304) in the eritoran group vs 26.9% (177/657) in the placebo group (P = 0.59; hazard ratio 1.05; 95% CI 0.88-1.26; difference in mortality rate, −1.1; 95% CI −5.3 to 3.1) or in the key secondary end point of 1-year all-cause mortality with 44.1% (290/657) in the eritoran group vs 43.3% (565/1304) in the placebo group, Kaplan-Meier analysis of time to death by 1 year, P = 0.79 (hazard ratio 0.98; 0.85-1.13). No significant differences were observed in any of the prespecified subgroups. Adverse events, including secondary infection rates, did not differ between study groups. Conclusion: Among patients with severe sepsis, eritoran did not result in reduced 28-day mortality.

Abstract:  Opal. Effect of Eritoran, an Antagonist of MD2-TLR4, on Mortality in Patients With Severe Sepsis: The ACCESS Randomized Trial. JAMA 2013;309(11):1154


Journal of the American Medical Association:     Heart Failure

Gheorghiade et al completed an international, double-blind, placebo-controlled study investigating whether aliskiren (150 mg, increased to 300 mg as tolerated), a direct renin inhibitor, when added to standard therapy, would reduce the rate of cardiovascular death or heart failure rehospitalization among hospitalized heart failure patients. 1639 patients were randomized, with 1615 patients included in the final efficacy analysis cohort (808 aliskiren, 807 placebo). Mean age was 65 years; mean LVEF, 28%; 41% of patients had diabetes mellitus, mean estimated glomerular filtration rate, 67 mL/min/1.73 m2. At admission and randomization, median NT-proBNP levels were 4239 pg/mL and 2718 pg/mL, respectively. In total, 24.9% of patients receiving aliskiren (77 cardiovascular  deaths, 153 heart failure rehospitalizations) and 26.5% of patients receiving placebo (85 cardiovascular deaths, 166 heart failure rehospitalizations) experienced the primary end point at 6 months (hazard ratio 0.92; 95% CI 0.76-1.12; P = 0.41). At 12 months, the event rates were 35.0% for the aliskiren group (126 cardiovascular deaths, 212 heart failure rehospitalizations) and 37.3% for the placebo group (137 cardiovascular deaths, 224 heart failure rehospitalizations; HR 0.93; 95% CI 0.79-1.09; P = 0.36). The rates of hyperkalemia, hypotension, and renal impairment/renal failure were higher in the aliskiren group compared with placebo. Conclusion:  Among patients hospitalized for HF with reduced LVEF, initiation of aliskiren in addition to standard therapy did not reduce CV death or HF rehospitalization at 6 months or 12 months after discharge.

Abstract:  Gheorghiade. Effect of Aliskiren on Postdischarge Mortality and Heart Failure Readmissions Among Patients Hospitalized for Heart Failure: The ASTRONAUT Randomized Trial. JAMA 2013;309(11):1125


Research Presented at the Brussels Symposium on Intensive Care and Emergency Medicine

Serlipressin in Septic Shock

Vincent et al presented a phase 1 trial of Serlipressin (selective V1 agonist) in septic shock. There is some animal data suggesting serlipressin may reduce vascular permeability & leak, reducing fluid requirements. Ten patients were treated with low dose serlipressin, and 19 at higher dose (2.5 ng/kg/min).  Serlipressin therapy was associated with decreased noradrenaline requirements, increased shock resolution at 48 hours, increased ventilator-free days at 7 days, and less positive fluid balance (6.5 vs 9L) at 7 days. A phase II trial is now planned.

Albumin in Severe Sepsis and Septic Shock  (ALBIOS Study)

Gattinoni presented the latest update from the ALBIOS study, a randomized controlled trial of albumin therapy targeted at serum Albumin >30g/L in patients with severe sepsis or septic shock in Italy. There were 903 patients in the Albumin group, and 907 in the crystalloid-only group. Doses of 200 or 300 ml 20% albumin were administered, depending on the serum albumin level in the treatment group. There was no overall 90-day mortality benefit (41.1 vs 43.6%). In pre-specified subgroup analysis:
  • Early (randomised within 6 hours) - no difference (mortality 40.6% in both groups)
  • Late (6-24 hours) - 41.3 vs 45% in favour of albumin (not significant)
  • Septic shock 90-day mortality 42.6% vs 48.4% (P=0.03)
  • Also benefit in subgroups with higher no of organ failures.

many thanks to JS for forwarding these results



Journal of the Royal College of Physicians of Edinburgh:     Acute Kidney Injury


Clinical Journal of the American Society of Nephrology:     Thallium Poisoning


Surgical Infections:    Antimicrobial Prophylaxis in Surgery

Review - Clinical


Frontiers in Neurology:     Traumatic Brain Injury


Frontiers in Neurology:     Functional MRI


International Journal of Critical Illness and Injury Science:     Embolic Disease


Clinical Cardiology:     Cardiac Valve Disease


Electrolytes and Blood Pressure:     Cardio-Renal Syndrome


InTech:     Cardiac Output Monitoring


InTech:     Biomarkers of Cardiac Ischaemia



Respirology:     Pulmonary Mesenchymal Stem Cells



Surgical Infections:     Silver as an Antimicrobial



Perioperative Medicine:     Postanaesthetic Care Unit


Swiss Medical Weekly:     Anaesthetic Safety


Review - Basic Science

The Open Biochemistry Journal:     Nitric Oxide


Critical Care Series

 Critical Care:    Annual Update in Intensive Care and Emergency Medicine 2013


Critical Care:     A selective look back and a glimpse forward



I hope you find these brief summaries and links useful.

Until next week