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Article 1
Effect of Systematic Intensive Care Unit Triage on Long-term Mortality Among Critically Ill Elderly Patients in France: A Randomized Clinical Trial. Guidet B, Leblanc G, Simon T, Woimant M, Quenot JP, Ganansia O, Maignan M, Yordanov Y, Delerme S, Doumenc B, Fartoukh M, Charestan P, Trognon P, Galichon B, Javaud N, Patzak A, Garrouste-Orgeas M, Thomas C, Azerad S, Pateron D, Boumendil A; ICE-CUB 2 Study Network. JAMA. 2017 Oct 17;318(15):1450-1459.
The ICE-CUB 2 study (Intensive Care for Elderly–CUB-Re´a 2) was a 3-year prospective cluster-randomized clinical trial (RCT). The RCT assigned critically ill elderly adults to two arms, as follows: 1) systematic ICU admission using a highly coordinated and multifaceted triage between emergency department (ED) physicians and ICU physicians or 2) standard practice and triage. Main inclusion criteria consisted of A) 75 years or older with critical illness arriving to an ED, B) preserved functional status, C) preserved nutritional status, and D) free of active cancer. Main exclusion criteria consisted of ED stay > 24h, a secondary ED referral, and refusal to participate. The primary outcome was overall mortality at 6 months. After adjustments for baseline characteristics, and consistent with the ICE-CUB 1 study, patients in the systematic strategy group had no significant increase in risk of death at 6 months (RR= 1.05; 95%CI:0.96-1.14).
This RCT was conducted in France from January 2012 to November 2015 among 24 hospitals consisting of 12 medical and 12 mixed ICUs ultimately enrolling 3037 critically ill elderly patients. There was only 1 patient withdrawal. The intervention of systematic and coordinated ED triage also led to higher ICU admission rates (i.e., nearly double) and led to higher in-hospital mortality. Compared to France, the US has at least three-fold higher ICU beds, and spends 50% its hospital expenditures on ICU care. This study should be interpreted carefully, as often, ICU care is appropriate for elderly patients, but resource allocation is important to understand particularly if intensive care has the potential to be ineffective (e.g., unhelpful, futile, harmful) - more is not necessarily better.
Additional Reference for Article 1:
Variability of intensive care admission decisions for the very elderly. Boumendil A, Angus DC, Guitonneau AL, Menn AM, Ginsburg C, Takun K, Davido A, Masmoudi R, Doumenc B, Pateron D, Garrouste-Orgeas M, Somme D, Simon T, Aegerter P, Guidet B; ICE-CUB study group. PLoS One. 2012;7(4):e34387.
Article 2
Age of Red Cells for Transfusion and Outcomes in Critically Ill Adults. Cooper DJ, McQuilten ZK, Nichol A, Ady B, Aubron C, Bailey M, Bellomo R, Gantner D, Irving DO, Kaukonen KM, McArthur C, Murray L, Pettilä V, French C; TRANSFUSE Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group. N Engl J Med. 2017 Nov 9;377(19):1858-1867.
The TRANSFUSE (Standard Issue Transfusion versus Fresher Red-Cell Use in Intensive Care)
study was a 4-year international, double-blinded, randomized clinical trial (RCT). The RCT assigned critically ill adults needing transfusion to two arms, as follows: 1) short-term red-cell storage group (e.g., freshest available) or 2) long-term red-cell storage group (e.g., oldest available). Main inclusion criteria consisted of A) critically ill adults, B) anticipated ICU stay >24h, C) clinical decision to transfuse red-cells. Main exclusion criteria consisted of prior red-cell transfusion, cardiac surgery in current admission, hematologic cancer, organ transplantation, pregnancy, expected death < 24h, objection to human blood products, participation in a competing study, and the opinion of lack of equipoise by the treating physician. The primary outcome was 90-day all-cause mortality. The age of transfused red cells did not affect 90-day mortality among critically ill adults (absolute risk difference= 0.7%; 95%CI: −1.7 to 3.1; P=0.57).
This RCT was conducted in five countries (Australia, New Zealand, Ireland, Finland, Saudi Arabia) and 59 centers from November 2012 to December 2016 ultimately randomizing 4994 critically ill adults with 98.5% (n=4919) included in the primary analysis. Red cells were all leukoreduced before storage with a minimum of 35-day shelf-life. Treating physicians determined timing and number of transfusion(s). Among the short-term storage group (n=2457), the mean storage duration was 11.8 days, the time from randomization to 1st transfusion was 1.6h, and they received a mean of 4 red-cell units. Among the long-term storage group (n=2462), the mean storage duration was 22.4 days, the time from randomization to 1st transfusion was 1.5h and they received a mean of 4 red-cell units. The study was powered to detect a 15% relative difference in mortality from a projected baseline mortality rate of 28% by 90 days. At 90 days post-randomization, death had occurred in 610 patients (24.8%) in the short-term storage group and in 594 (24.1%) in the long-term storage group. Sensitivity analyses did not change the outcome and accounted for severity of illness, hemoglobin level, blood group, site, and age. There were no differences in the pre-specified secondary outcomes (e.g., 28-day mortality; persistent organ dysfunction at day 28, new bloodstream infections, mechanical ventilation, renal-replacement therapy, ICU length of stay). The TRANSFUSE study builds on the findings of The Age of Blood Evaluation (ABLE) trial and the Informing Fresh versus Old Red Cell Management (INFORM) trial; there is no clinically meaningful benefit of transfusion with freshest available units of stored red-cells.
Additional References for Article 2:
Age of transfused blood in critically ill adults. Lacroix J, He´bert PC, Fergusson DA, et al. N Engl J Med 2015;372:1410-8.
Effect of short-term vs. long-term blood storage on mortality after transfusion. Heddle NM, Cook RJ, Arnold DM, et al. N Engl J Med. 2016;375:1937-45.
Article 3
Enteral versus parenteral early nutrition in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2). Reignier J, Boisramé-Helms J, Brisard L, Lascarrou JB, Ait Hssain A, Anguel N, Argaud L, Asehnoune K, Asfar P, Bellec F, Botoc V, Bretagnol A, Bui HN, Canet E, Da Silva D, Darmon M, Das V, Devaquet J, Djibre M, Ganster F, Garrouste-Orgeas M, Gaudry S, Gontier O, Guérin C, Guidet B, Guitton C, Herbrecht JE, Lacherade JC, Letocart P, Martino F, Maxime V, Mercier E, Mira JP, Nseir S, Piton G, Quenot JP, Richecoeur J, Rigaud JP, Robert R, Rolin N, Schwebel C, Sirodot M, Tinturier F, Thévenin D, Giraudeau B, Le Gouge A; NUTRIREA-2 Trial Investigators; Clinical Research in Intensive Care and Sepsis (CRICS) group. Lancet. 2018 Jan 13;391(10116):133-143.
The NUTRIREA-2 study was a 2-year open-label double-blinded, randomized clinical trial (RCT). The RCT assigned critically ill adults to two arms of early isocaloric nutrition routes, as follows: 1) enteral or 2) parenteral. Main inclusion criteria consisted of A) Adults in Concomittant respiratory failure and shock (requiring mechanical ventilation and vasopressors), and B) Nutrition to be started within 24h of intubation. Main exclusion criteria consisted of mechanical ventilation >24h ago, recent GI surgery (<1 month), history of upper GI surgery, pre-existing enteral/parenteral nutrition, pregnancy, and contraindication to parenteral nutrition. The primary outcome was 28-day mortality. Early isocaloric enteral nutrition did not reduce 28-day mortality (absolute difference estimate 2.0%; 95%CI: −1.9 to 5.8; P=0.33).
This RCT was conducted in France among 44 ICUs from March 2013 to June 2015 intending to randomize 2854 critically ill adults. The study was powered to detect a 5% decrease in mortality in the parenteral group from a projected baseline mortality rate of 37% at 28 days in the enteral group. Median time from intubation to initiation of nutritional support was 16.2h (IQR 8.9–21.7) in the enteral group and 16.1h (9.9–22.0) in the parenteral group. At baseline, median baseline norepinephrine dose was 0.56 mcg/kg/min (0.3-1.2) in the enteral group and 0.50 mcg/kg/min (0.25-1.03) in the parenteral group, although both groups may have used other pressors alone or in conjunction. However, the trial was terminated after the second pre-planned interim analysis, as by day 28, 443 (37%) of 1202 patients in the enteral group and 422 (35%) of 1208 patients in the parenteral group had died. ICU-acquired infections (i.e., composite outcome of ventilator-associated pneumonia, bacteremia, urinary tract infections, catheter-related infections, and other infections) did not significantly differ between groups. Compared with the parenteral group, the enteral group had higher incidences of patients with vomiting (406 [34%] vs. 246 [20%]; HR=1.89, 95%CI:1.62–2.20; P<0.0001), diarrhea (432 [36%] vs. 393 [33%]; HR=1.20, 95%CI:1.05–1.37]; P=0.009), bowel ischemia (19 [2%] vs. 5 [<1%]; HR=3.84, 95%CI:1.43–10.3]; P=0.007), and acute colonic pseudo-obstruction (11 [1%] vs. 3 [<1%]; HR=3.7, 95%CI:1.03–13.2; P=0.04). In this study, early enteral nutrition may increase adverse GI events, and in line with many recent RCTs, early nutrition interventions do not appear to save lives in the ICU.
Additional References for Article 3:
Impact of early enteral versus parenteral nutrition on mortality in patients requiring mechanical ventilation and catecholamines: study protocol for a randomized controlled trial (NUTRIREA2). Brisard L, Le Gouge A, Lascarrou JB, Dupont H, Asfar P, Sirodot M, Piton G, Bui HN, Gontier O, Hssain AA, Gaudry S, Rigaud JP, Quenot JP, Maxime V, Schwebel C, Thévenin D, Nseir S, Parmentier E, El Kalioubie A, Jourdain M, Leray V, Rolin N, Bellec F, Das V, Ganster F, Guitton C, Asehnoune K, Bretagnol A, Anguel N, Mira JP, Canet E, Guidet B, Djibre M, Misset B, Robert R, Martino F, Letocart P, Silva D, Darmon M, Botoc V, Herbrecht JE, Meziani F, Devaquet J, Mercier E, Richecoeur J, Martin S, Gréau E, Giraudeau B, Reignier J. Trials 2014; 15: 507.
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