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Critical Care Reviews Newsletter

March 20th 2013



Welcome to the 67th 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.

Apologies for being a few days late, a combination of exams and a viral illness which felt like ebola.

It's been a busy week for critical care research with numerous studies being published, including investigations into darbopoietin, several studies on PCI, glutamine, cardiac arrest, subclavian vein catheterization and UK studies describing the incidence of awareness under general anaesthesia and the current management of acute kidney injury. There is also further work from the FEAST investigators, plus a commentary discussing their latest work.

The American Heart Association has published a consensus statement on post-cardiac arrest management. There are also editorials, commentaries, including a paper on anaesthetists as perioperative physicians, and study critiques on both PROWESS SHOCK and 6S. There is also the usual wide range of clinical review articles, in addition to basic science reviews and non-clinical reviews.

The topic for This Week's Papers is a series from Critical Care, "A selective look back and a glimpse forward", with today's Paper of the Day looking at haemodynamic targets.

Presentations from the Association of Anaesthetists of Great Britain and Ireland Winter Scientific meeting, plus previous meetings, have been added to the vodcasts page.



New England Journal of Medicine:     Darbepoetin in Critical Care Anaemia

Swedberg et al completed a randomized, double-blind trial in 2278 patients with systolic heart failure and mild-to-moderate anemia (hemoglobin level, 9.0 to 12.0 g per deciliter) to evaluate the effect of darbepoetin alfa (to achieve a hemoglobin target of 13 g per deciliter) using a composite of death from any cause or hospitalization for worsening heart failure. There was no difference in primary outcome (darbepoetin alfa group 50.7% versus control group 49.5%) (hazard ratio in the darbepoetin alfa group, 1.01; 95% CI, 0.90 to 1.13; P=0.87). There was no significant between-group difference in any of the secondary outcomes. The neutral effect of darbepoetin alfa was consistent across all prespecified subgroups. There was also no difference in fatal or nonfatal strokes (darbepoetin alfa group 3.7% versus control group 2.7%) (P=0.23). There were more thromboembolic adverse events in the darbepoetin alfa group (13.5% versus 10.0%, p=0.01). Cancer-related adverse events were similar in the two study groups.  Conclusion: Treatment with darbepoetin alfa did not improve clinical outcomes in patients with systolic heart failure and mild-to-moderate anemia.

Full Text:  Swedberg. Treatment of Anemia with Darbepoetin Alfa in Systolic Heart Failure. N Eng J Med 2013; epublished March 10th


New England Journal of Medicine:     Percutaneous Coronary Intervention

Armstrong and colleagues randomized 1892 patients with STEMI who presented within 3 hours after symptom onset and who were unable to undergo primary PCI within 1 hour, patients to either primary PCI or fibrinolytic therapy with bolus tenecteplase (amended to half dose in patients ≥75 years of age), clopidogrel, and enoxaparin before transport to a PCI-capable hospital. Emergency coronary angiography was performed if fibrinolysis failed; otherwise, angiography was performed 6 to 24 hours after randomization. There was no difference in primary end point of composite of death, shock, congestive heart failure, or reinfarction up to 30 days (fibrinolysis 12.4% versus primary PCI group 14.3%; relative risk in the fibrinolysis group, 0.86; 95% confidence interval, 0.68 to 1.09; P=0.21). Emergency angiography was required in 36.3% of patients in the fibrinolysis group, whereas the remainder of patients underwent angiography at a median of 17 hours after randomization. More intracranial hemorrhages occurred in the fibrinolysis group than in the primary PCI group (1.0% vs. 0.2%, P=0.04; after protocol amendment, 0.5% vs. 0.3%, P=0.45). The rates of nonintracranial bleeding were similar in the two groups. Conclusion: Prehospital fibrinolysis with timely coronary angiography resulted in effective reperfusion in patients with early STEMI who could not undergo primary PCI within 1 hour after the first medical contact, but was associated with a slightly increased risk of intracranial bleeding.

Full Text:  Armstrong. Fibrinolysis or Primary PCI in ST-Segment Elevation Myocardial Infarction. N Eng J Med 2013; epublished March 10th


Bhatt et al completed a double-blind, placebo-controlled trial in 11,145 patients undergoing either urgent or elective PCI and were receiving guideline-recommended therapy to receive either a bolus and infusion of cangrelor or to receive a loading dose of 600 mg or 300 mg of clopidogrel. Cangrelor therapy was associated with a reduced incidence of the primary outcome (a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis) than clopidogrel therapy (4.7% versus 5.9%; adjusted odds ratio with cangrelor, 0.78; 95% CI 0.66 to 0.93; P=0.005). There was no difference in severe bleeding (cangrelor 0.16% versus clopidogrel 0.11%; odds ratio 1.50; 95% CI 0.53 to 4.22; P=0.44). Stent thrombosis occurred less often in the  cangrelor group 0.8% versus 1.4%; odds ratio 0.62; 95% CI 0.43 to 0.90; P=0.01). Conclusion: In comparison with clopidogrel, cangrelor significantly reduced the rate of ischemic events, including stent thrombosis, during PCI, with no significant increase in severe bleeding.

Full Text: Bhatt. Effect of Platelet Inhibition with Cangrelor during PCI on Ischemic Events. N Eng J Med 2013; epublished March 10th


As emergency surgery is a rare event after percutaneous coronary intervention (PCI), Jacobs and colleagues performed a randomized controlled trial,  in a 3:1 ratio, comparing nonemergency PCI at hospitals without on-site cardiac surgery (n=2274) with nonemergency PCI at hospitals with on-site cardiac surgery (n=917). There was no difference in major adverse cardiac events at 30 days (without on-site cardiac surgery 9.5% versus on-site cardiac surgery 9.4%; relative risk, 1.00; 95% one-sided upper CI 1.22; P<0.001 for noninferiority) or at 1 year (17.3% versus 17.8%, respectively, RR 0.98; 95% one-sided upper CI 1.13; P<0.001 for noninferiority). The rates of death, myocardial infarction, repeat revascularization, and stroke (the components of the primary end point) did not differ significantly between the groups at either time point. Conclusion: Nonemergency PCI procedures performed at hospitals without on-site cardiac surgical services were noninferior to procedures performed at hospitals with on-site surgical services.

Full Text:  Jacobs. Nonemergency PCI at Hospitals with or without On-Site Cardiac Surgery. N Eng J Med 2013; epublished March 11th


Critical Care:     Neuromuscular Blocking Agents in ARDS

Alhazzani and colleagues conducted a systematic review and meta-analysis, including 3 studies (n=431), to evaluate to effects of 48-hour infusions of cisatracurium besylate in adults with acute respiratory distress syndrome. This short-term neuromuscular blockade was associated with lower hospital mortality (RR 0.72; 95% CI 0.58 to 0.91; p=0.005; I2=0%) and lower risk of barotrauma (RR 0.43; 95% CI 0.20 to 0.90; P=0.02; I2=0%). This intervention had no effect on either the duration of mechanical ventilation among survivors (MD 0.25 days; 95% CI - 5.48, 5.99; p=0.93; I2=49%), or the risk of ICU-acquired weakness (RR 1.08; 95% CI 0.83 to 1.41; p =0.57; I2= 0%). Conclusion: Short-term infusion of cisatracurium besylate reduces hospital mortality and barotrauma, and does not appear to increase ICU-acquired weakness for critically ill adults with ARDS.

Full Text:  Alhazzani. Neuromuscular blocking agents in acute respiratory distress syndrome: a systematic review and meta-analysis of randomized controlled trials. Critical Care 2013;17:R43


Clinical Nutrition:     Glutamine

In a systematic review and meta analysis of 40 trials, parenteral glutamine supplementation was not associated with a reduction in short-term mortality (RR = 0.89; 95% CI, 0.77–1.04), although both the rate of infections (RR = 0.83; 95% CI, 0.72–0.95) and length of hospital stay (2.35 days shorter; 95% CI, −3.68 to −1.02) were significantly reduced. The meta-analysis results were strongly influenced by one recent trial. Conclusion: In the critically ill, parenteral glutamine is associated with reductions in infectious complications and shorter duration of hospital stay, but not reduced mortality.

Full Text:  Bollhalder. A systematic literature review and meta-analysis of randomized clinical trials of parenteral glutamine supplementation. Clinical Nutrition 2013;32(2):213-223


New England Journal of Medicine:     Elderly Cardiac Arrest Survivors

Using data from a national registry of inpatient cardiac arrests, Chan et al identified 6972 adults, 65 years of age or older, who were discharged from the hospital after surviving an in-hospital cardiac arrest. One year after hospital discharge, 58.5% of the patients were alive, and 34.4% had not been readmitted to the hospital. The risk-adjusted rate of 1-year survival was lower among older patients than among younger patients (63.7%, 58.6%, and 49.7% among patients 65 to 74, 75 to 84, and ≥85 years of age, respectively; P<0.001), among men than among women (58.6% vs. 60.9%, P=0.03), and among black patients than among white patients (52.5% vs. 60.4%, P=0.001). The risk-adjusted rate of 1-year survival was 72.8% among patients with mild or no neurologic disability at discharge, as compared with 61.1% among patients with moderate neurologic disability, 42.2% among those with severe neurologic disability, and 10.2% among those in a coma or vegetative state (P<0.001 for all comparisons). Moreover, 1-year readmission rates were higher among patients who were black, those who were women, and those who had substantial neurologic disability (P<0.05 for all comparisons). These differences in survival and readmission rates persisted at 2 years. At 3 years, the rate of survival among survivors of in-hospital cardiac arrest was similar to that of patients who had been hospitalized with heart failure and were discharged alive (43.5% and 44.9%, respectively; risk ratio, 0.98; 95% confidence interval, 0.95 to 1.02; P=0.35). Conclusion: In elderly patients discharged home post cardiac arrest, one year and three year survival rates were 58.5% and 43.5%, respectively.

Abstract: Chan. Long-Term Outcomes in Elderly Survivors of In-Hospital Cardiac Arrest. N Engl J Med 2013;368:1019-1026


New England Journal of Medicine:     Family Presence during CPR

Jabre et al performed a prospective randomized controlled trial to assess the impact of family presence during CPR on both family members (n=570) and the medical team (15 prehospital emergency medical service teams). In the intervention group, 211 of 266 relatives (79%) witnessed CPR, as compared with 131 of 304 relatives (43%) in the control group. In the intention-to-treat analysis, the frequency of post-traumatic stress disorder-related symptoms was significantly higher in the control group than in the intervention group (adjusted odds ratio, 1.7; 95% CI 1.2 to 2.5; P=0.004) and among family members who did not witness CPR than among those who did (adjusted odds ratio, 1.6; 95% CI, 1.1 to 2.5; P=0.02). Family-witnessed CPR did not affect resuscitation characteristics, patient survival, or the level of emotional stress in the medical team and did not result in medicolegal claims. Conclusion: Family presence during at-home CPR is associated with reduced post-traumatic stress disorder-related symptoms while having no effect on medical team emotional stress, resuscitation or patient outcome.

Abstract: Jabre. Family Presence during Cardiopulmonary Resuscitation. N Engl J Med 2013;368:1008-1018


BMC Medicine:     FEAST Study

In a post-hoc analysis of the FEAST study, Maitland and colleagues explored the effect of fluid boluses on 48-hour all-cause mortality by clinical presentation at enrolment, hemodynamic changes over the first hour, and on different modes of death, according to terminal clinical events. Of 2,396 out of 3,141 (76%) classifiable participants, 1,647 (69%) had a severe metabolic acidosis or severe shock, 625 (26%) had a respiratory syndrome and 976 (41%) had a neurological syndrome, either alone or in combination. Mortality was greatest among children fulfilling criteria for all three organ syndromes (28% bolus, 21% control) and lowest for lone respiratory (2% bolus, 5% control) or neurological (3% bolus, 0% control) syndromes. Excess mortality in bolus arms versus control was apparent for all three syndromes, including all their component features. By one hour, shock had resolved (responders) more frequently in bolus versus control groups (43% versus 32%, P <0.001), but excess mortality with boluses was evident in responders (RR 1.98; 95% CI 0.94 to 4.17; P = 0.06) and 'non-responders' (RR 1.67; 95% CI 1.23 to 2.28; P = 0.001), with no evidence of heterogeneity (P = 0.68). The major difference between bolus and control arms was the higher proportion of cardiogenic or shock terminal clinical events in bolus arms (n = 123; 4.6% versus 2.6%, P = 0.008) rather than respiratory (n = 61; 2.2% versus 1.3%, P = 0.09) or neurological (n = 63, 2.1% versus 1.8%, P = 0.6) terminal clinical events.  Conclusion: Cardiovascular collapse rather than fluid overload appeared to contribute most to excess deaths with rapid fluid resuscitation.

Full Text:  Maitland. Exploring mechanisms of excess mortality with early fluid resuscitation: insights from the FEAST trial. BMC Medicine 2013; 11:68


British Journal of Anaesthesia:     Awareness 

Pandit et al performed a national survery to establish the incidence of awareness during general anaesthesia in the UK. There were 153 new cases of accidental awareness notified to respondents in 2011, an estimated incidence of 1:15 414, lower than the 1-2:1000 previously reported in prospective clinical trials. Almost half the cases (72, 47%) occurred at or after induction of anaesthesia but before surgery, with 46 (30%) occurring during surgery and 35 (23%) after surgery before full recovery. Awareness during surgery appeared to lead more frequently to pain or distress than at induction and emergence (62% vs 28% and 23%, respectively). Depth of anaesthesia monitors were available in 164 centres (62%), but routinely used by only 132 (1.8%) of anaesthetists.

Full Text:  Pandit. A national survey of anaesthetists (NAP5 Baseline) to estimate an annual incidence of accidental awareness during general anaesthesia in the UK. Br J Anaesth 2013; epublished March 12th


British Journal of Anaesthesia:     Subclavian Vein Catheterization

Kim and colleagues performed a randomized trial in 362 patients undergoing elective surgery, to assess whether, for subclavian vein catheterization, the neutral shoulder position (n=181) would not be inferior to the retracted shoulder position (n=181), created by the placement of a 1 litre saline bag longitudinally beneath the spinal column and between the scapulae. There was no difference in success rates  between the neutral (95.6%) and retracted groups (96.1%). There were four catheterization failures (2.2%) in the neutral group and two failures (1.1%) in the retracted group. Complication rates were not significantly different between the neutral and retracted groups; (1.7% vs 2.2%) for arterial punctures and (0.6% vs 0.6%) for pneumothorax. Conclusion: The neutral shoulder position was as effective as the retracted shoulder position for infraclavicular subclavian venous catheterization.

Abstract:  Kim. Comparison of the neutral and retracted shoulder positions for infraclavicular subclavian venous catheterization: a randomized, non-inferiority trial. Br J Anaesth 2013; epublished March 10th


Nephrology Dialysis Transplantation:    Acute Kidney Injury in the UK

Jones and colleagues completed an online survey of all general adult UK ICUs to determine how acute kidney injury is investigated and managed.  One hundred and eighty-eight out of two hundred and thirty-three units (80%) started the survey; 167 (72%) completed it. Only 19.2% of respondents routinely use AKIN or Risk, Injury, Failure, Loss, End-stage kidney disease (RIFLE) criteria for diagnosis and staging of AKI. A nephrologist is never or rarely consulted about patients with AKI in over 40% of the units. Only 46.4% have 24-h access to a renal ultrasound service. Continuous venovenous haemofiltration (CVVH) is the most commonly used form of renal replacement therapy (RRT) but intermittent haemodialysis (IHD) is used infrequently. Continuous RRTs (CRRTs) are managed almost exclusively by intensivists, whereas IHD is managed predominantly by nephrologists. The most frequently used criteria for initiating RRT are hyperkalaemia, fluid overload and pH. Most units have a standard RRT protocol and 35 mL/kg/h is the most frequently prescribed dose of CVVH. Only 51% of the units assess the delivered dose of RRT. Conclusion: Considerable variation exists in the investigation and management of AKI in UK ICUs.

Abstract:  Jones. How acute kidney injury is investigated and managed in UK intensive care units—a survey of current practice. Nephrol Dial Transplant 2013; epublished March 8th


Journal of the American Medical Association:     Sildenafil for Diastolic Heart Failure

Redfield et al undertook a multicenter, double-blind, placebo-controlled, parallel-group, randomized clinical trial in stable outpatients with heart failure with preserved ejection fraction to determine the effect of sildenafil (n=113) compared with placebo (n=103). Sildenafil was administered orally at 20 mg, 3 times daily for 12 weeks, followed by 60 mg, 3 times daily for 12 weeks. Median age was 69 years, and 48% of patients were women.  At 24 weeks, there was no difference in peak oxygen consumption, clinical status or exercise capacity. Adverse events occurred in 78 placebo patients (76%) and 90 sildenafil patients (80%). Serious adverse events occurred in 16 placebo patients (16%) and 25 sildenafil patients (22%). Conclusion:  Among patients with HFPEF, phosphodiesterase-5 inhibition with administration of sildenafil for 24 weeks, compared with placebo, did not result in significant improvement in exercise capacity or clinical status.

Full Text: Redfield. Effect of Phosphodiesterase-5 Inhibition on Exercise Capacity and Clinical Status in Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial. JAMA 2013; epublished March 11th


Journal of the American Medical Association:     Percutaneous Coronary Intervention

Chhatriwalla and colleagues used data from the American CathPCI Registry to describe the association between bleeding events and in-hospital mortality after PCI. There were 57 246 bleeding events (1.7%) and 22 165 in-hospital deaths (0.65%) in 3 386 688 PCI procedures. The adjusted population attributable risk for mortality related to major bleeding was 12.1% (95% CI, 11.4%-12.7%) in the entire CathPCI cohort. The propensity-matched population consisted of 56 078 procedures with a major bleeding event and 224 312 controls. In this matched cohort, major bleeding was associated with increased in-hospital mortality (5.26% vs 1.87%; risk difference, 3.39% [95% CI, 3.20%-3.59%]; number needed to harm (NNH) = 29 [95% CI, 28-31]; P < .001). The association between major bleeding and in-hospital mortality was observed in all strata of preprocedural bleeding risk. Although both access-site and non–access-site bleeding were associated with increased in-hospital mortality (2.73% vs 1.87%; risk difference, 0.86% [95% CI, 0.66%-1.05%], NNH = 117 [95% CI, 95-151], P < .001; and 8.25% vs 1.87%; risk difference, 6.39% [95% CI, 6.04%-6.73%], NNH = 16 [95% CI, 15-17], P < .001, respectively), the NNH was lower for nonaccess bleeding. Conclusion: In a large registry of patients undergoing PCI, postprocedural bleeding events were associated with increased risk of in-hospital mortality, with an estimated 12.1% of deaths related to bleeding complications.

Abstract: Chhatriwalla. Association Between Bleeding Events and In-hospital Mortality After Percutaneous Coronary Intervention. JAMA 2013;309(10):1022


Consensus Statement

Circulation:     Post-Cardiac Arrest Management



Texas Heart Institution Journal:     Pulmonary Embolism


Respirology:     Cystic Fibrosis in ICU


Anaesthesia Essays and Researches:     Medical Writing


Study Critique

Critical Care:     PROWESS-Shock


Critical Care:     6S



Journal of the American Medical Association:     Surviving Sepsis Campaign


BMC Anaesthesiology:     Anaesthetists as Perioperative Physicians


Antimicrobial Agents and Chemotherapy:     Fungal Meningitis Outbreak


Review - Clinical


Neurology Research International:     Cerebral Vasospasm


Journal of NeuroInterventional Surgery:     Stroke Imaging


Stroke Research and Treatment:     Cardiac Arrest & Subarachnoid Haemorrhage


Stroke Research and Treatment:     MicroRNAs in Cerebral Ischaemia



European Heart Journal:     Iron in Heart Failure


International Journal of Gerontology:     Heart Failure with Preserved Ejection Fraction


Medical Devices: Evidence and Research:     Coronary Artery Disease


Circulation:     Invasive Cardiopulmonary Test



Tuberculosis and Respiratory Diseases:     Eosinophilic Pneumonia



Therapeutic Advances in Gastroenterology:     Enteral Nutrition



Journal of the Formosan Medical Association:     Fluid Therapy in Acute Kidney Injury


Clinical Journal of the American Society of Nephrology:     Acute Kidney Injury


Blood Purification:     On-Line Haemodilution



Journal of Blood Disorders and Transfusion:     Transfusion in Sepsis


Journal of Blood Disorders and Transfusion:     Blood Processing



PLoS Pathogen:     Fungal Pathophysiology



Revista Brasileira de Anestesiologia:     Analgesia in Burns



Stroke Research and Treatment:     Neonatal Hypoxic Encephalopathy



Anaesthesia Essays and Researches:     Anaphylaxis



New England Journal of Medicine:     Family Presence during CPR


Stem Cells International:     Regenerative Medicine


Review - Basic Science

Journal of the American Medical Association:     Genomics


Postgraduate Medical Journal:     MRI


Review - Non-Clinical

New England Journal of Medicine:     Patient Data


New England Journal of Medicine:     Physician Incentives


New England Journal of Medicine:     Health Planning


Nigerian Journal of Basic and Clinical Sciences:     Undergraduate Assessment


Anaesthesia Essays and Researches:     Simulation



I hope you find these brief summaries and links useful.

Until next week