ICMWK favourite 10ish studies from 2014

Prospective trials (no MA/SR/reviews). In random order:

1. High versus low positive end-expiratory pressure during general anaesthesia for open abdominal surgery (PROVHILO trial): a multicentre randomised controlledtrial.

Lancet. 2014 Aug 9;384(9942):495-503. doi: 10.1016/S0140-6736(14)60416-5.

PROVE Network Investigators for the Clinical Trial Network of the European Society of Anaesthesiology, Hemmes SN et al,


BACKGROUND: The role of positive end-expiratory pressure in mechanical ventilation during general anaesthesia for surgery remains uncertain. Levels of pressure higher than 0 cm H2O might protect against postoperative pulmonary complications but could also cause intraoperative circulatory depression and lung injury from overdistension. We tested the hypothesis that a high level of positive end-expiratory pressure with recruitment manoeuvres protects against postoperative pulmonary complications in patients at risk of complications who are receiving mechanical ventilation with low tidal volumes during general anaesthesia for open abdominal surgery.

INTERPRETATION: A strategy with a high level of positive end-expiratory pressure and recruitment manoeuvres during open abdominal surgery does not protect against postoperative pulmonary complications. An intraoperative protective ventilation strategy should include a low tidal volume and low positive end-expiratory pressure, without recruitment manoeuvres.

Applying slightly extreme settings to a large, random group. It would have been surprising if they found a positive difference. The whole point of a good ventilator strategy – or any medical treatment – is to have some guidelines, often set by big trials, and then individualise as you apply your clinical knowledge to each patient. Keeping a PEEP of 12 with circulatory effects in an otherwise healthy patient doesn’t make sense. Applying PEEP of 12 and recruitment maneuvers on indication in selected patients might well be a good strategy, even if applying these settings categorically to large, random groups of patients is a bad idea.

From Scancrit review


2. High-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition and nosocomial infections in the ICU: a randomized clinical trial.

JAMA. 2014 Aug 6;312(5):514-24. doi: 10.1001/jama.2014.7698

van Zanten AR et al. MetaPlus study.

IMPORTANCE: Enteral administration of immune-modulating nutrients (eg, glutamine, omega-3 fatty acids, selenium, and antioxidants) has been suggested to reduce infections and improve recovery from critical illness. However, controversy exists on the use of immune-modulating enteral nutrition, reflected by lack of consensus in guidelines. OBJECTIVE: To determine whether high-protein enteral nutrition enriched with immune-modulating nutrients (IMHP) reduces the incidence of infections compared with standard high-protein enteral nutrition (HP) in mechanically ventilated critically ill patients.

CONCLUSIONS AND RELEVANCE: Among adult patients breathing with the aid of mechanical ventilation in the ICU, IMHP compared with HP did not improve infectious complications or other clinical end points and may be harmful as suggested by increased adjusted mortality at 6 months. These findings do not support the use of IMHP nutrients in these patients


The MetaPlus trial results add to the possible harmful effects reported in at least 3 recent, large, multicenter trials on immunonutrition: the REDOXS, EDEN-OMEGA, and SIGNET trials, showing no benefit or possibly harmful effects. See also PulmCCM nutrition


3. High versus low blood-pressure target in patients with septic shock.

N Engl J Med. 2014 Apr 24;370(17):1583-93. doi: 10.1056/NEJMoa1312173.

Asfar P et al. SEPSISPAM Investigators.

BACKGROUND: The Surviving Sepsis Campaign recommends targeting a mean arterial pressure of at least 65 mm Hg during initial resuscitation of patients with septic shock. However, whether this blood-pressure target is more or less effective than a higher target is unknown.

CONCLUSIONS: Targeting a mean arterial pressure of 80 to 85 mm Hg, as compared with 65 to 70 mm Hg, in patients with septic shock undergoing resuscitation did not result in significant differences in mortality at either 28 or 90 days.


Due to a lower mortality than predicted the study was under-powered.

16.5% of patients in the high MAP group vs. 10.3% (P=0.01) in the low MAP group failed to achieve target BP because the attending clinician decided to limit the vasopressor infusion. Whilst this is an ethically important safety factor, this compliance bias will favour the null hypothesis.

For the majority of patients in septic shock a target MAP of 65-70 is a good starting point. However, in patients with chronic hypertension I will target a higher MAP. This is because, even though this did not improve mortality, it did reduce the need for renal replacement therapy with a NNT of 9.5.

From Wessex Bottom Line review


4. A randomized trial of protocol-based care for early septic shock.

N Engl J Med. 2014 May 1;370(18):1683-93. doi: 10.1056/NEJMoa1401602.

ProCESS Investigators. Yealy DM et al.

BACKGROUND: In a single-center study published more than a decade ago involving patients presenting to the emergency department with severe sepsis and septic shock, mortality was markedly lower among those who were treated according to a 6-hour protocol of early goal-directed therapy (EGDT), in which intravenous fluids, vasopressors, inotropes, and blood transfusions were adjusted to reach central hemodynamic targets, than among those receiving usual care. We conducted a trial to determine whether these findings were generalizable and whether all aspects of the protocol were necessary.

CONCLUSIONS: In a multicenter trial conducted in the tertiary care setting, protocol-based resuscitation of patients in whom septic shock was diagnosed in the emergency department did not improve outcomes.

 Mortality ~20% but initial power calculation based on 30–46%, therefore interim adjustment made and recruitment target reduced. Adherence to protocol was 88.1% in EGDT group and 95.6% in protocol-based standard therapy group. Although pragmatic, this is not perfect and may reduce between group differences.

So adults with sepsis in the ED have ~20% 60-day mortality and providing care by a dedicated team following either a strict or relaxed protocol makes no difference to this.

From The Bottom Line review


5. Hemicraniectomy in older patients with extensive middle-cerebral-artery stroke.

N Engl J Med. 2014 Mar 20;370(12):1091-100. doi: 10.1056/NEJMoa1311367.

Jüttler E et al. DESTINY II Investigators.

BACKGROUND: Early decompressive hemicraniectomy reduces mortality without increasing the risk of very severe disability among patients 60 years of age or younger with complete or subtotal space-occupying middle-cerebral-artery infarction. Its benefit in older patients is uncertain.

CONCLUSIONS: Hemicraniectomy increased survival without severe disability among patients 61 years of age or older with a malignant middle-cerebral-artery infarction. The majority of survivors required assistance with most bodily needs.

Although a clear mortality benefit there remains a high level of disability in the majority of these survivors – more than 90% had a functional outcome of worse than moderate disability.

Review paper

6. Fibrinolysis for patients with intermediate-risk pulmonary embolism

N Engl J Med. 2014 Apr 10;370(15):1402-11. doi: 10.1056/NEJMoa1302097.

Meyer G et al. PEITHO Investigators.

BACKGROUND: The role of fibrinolytic therapy in patients with intermediate-risk pulmonary embolism is controversial.

CONCLUSIONS: In patients with intermediate-risk pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke.

Composite outcome is problematic here. Surprisingly low incidence of haemodynamic support requirement. Not powered to determine mortality benefit. The inclusion criteria of up to 15 days for tenecteplase could outweigh benefits at this late stage

Tenecteplase for intermediate risk PE improved haemodynamics but resulted in 10 times the intracranial haemorrhage (2% vs. 0.2%) and 5 times the major haemorrhage (6.3% vs. 1.2%).

Also look at TOPCOAT, with great review by The Bottom Line.


7. Lower versus higher hemoglobin threshold for transfusion in septic shock.

N Engl J Med. 2014 Oct 9;371(15):1381-91. doi: 10.1056/NEJMoa1406617.

Holst LB et al. TRISS Trial Group; Scandinavian Critical Care Trials Group.

BACKGROUND: Blood transfusions are frequently given to patients with septic shock. However, the benefits and harms of different hemoglobin thresholds for transfusion have not been established.

CONCLUSIONS: Among patients with septic shock, mortality at 90 days and rates of ischemic events and use of life support were similar among those assigned to blood transfusion at a higher hemoglobin threshold and those assigned to blood transfusion at a lower threshold; the latter group received fewer transfusions.

Hb target of 7 equivalent to 9.

Protocol violations may have reduced power. 10% of patients in the low Hb threshold group got blood whilst above the threshold. Patients with bleeding or acute coronary syndromes excluded.

Now TRISS, ProCESS and ARISE agree on a target of 7.

Bottom line and PulmCCM reviews


8. Trial of the route of early nutritional support in critically ill adults.

N Engl J Med. 2014 Oct 30;371(18):1673-84. doi: 10.1056/NEJMoa1409860.

Harvey SE et al. CALORIES Trial Investigators.

BACKGROUND: Uncertainty exists about the most effective route for delivery of early nutritional support in critically ill adults. We hypothesized that delivery through the parenteral route is superior to that through the enteral route.

CONCLUSIONS: We found no significant difference in 30-day mortality associated with the route of delivery of early nutritional support in critically ill adults.

 Not blinded. Caloric targets were unmet in in both groups (<50%). Why not in the PN group?

“Early nutritional support through the parenteral route is neither more harmful nor more beneficial than through the enteral route. Enteral feeding does increase episodes of vomiting and hypoglycaemia but with no evidence of harm or nosocomial infection. “

Wessex Bottom line


9. Goal-directed resuscitation for patients with early septic shock.

N Engl J Med. 2014 Oct 16;371(16):1496-506. doi: 10.1056/NEJMoa1404380.

ARISE Investigators; ANZICS Clinical Trials Group, Peake SL et al.

BACKGROUND: Early goal-directed therapy (EGDT) has been endorsed in the guidelines of the Surviving Sepsis Campaign as a key strategy to decrease mortality among patients presenting to the emergency department with septic shock. However, its effectiveness is uncertain.

CONCLUSIONS: In critically ill patients presenting to the emergency department with early septic shock, EGDT did not reduce all-cause mortality at 90 days.


Less sick patients than ProCESS and Rivers. ‘Usual care’ is now quite different. Early identification, source control, antimicrobials and some fluid resuscitation seem to be what makes the real difference.

Wessex Bottom line review here


10. Early versus on-demand nasoenteric tube feeding in acute pancreatitis.

N Engl J Med. 2014 Nov 20;371(21):1983-93. doi: 10.1056/NEJMoa1404393.

Bakker OJ et al. Dutch Pancreatitis Study Group.

BACKGROUND: Early enteral feeding through a nasoenteric feeding tube is often used in patients with severe acute pancreatitis to prevent gut-derived infections, but evidence to support this strategy is limited. We conducted a multicentre, randomized trial comparing early nasoenteric tube feeding with an oral diet at 72 hours after presentation to the emergency department in patients with acute pancreatitis.

CONCLUSIONS: This trial did not show the superiority of early nasoenteric tube feeding, as compared with an oral diet after 72 hours, in reducing the rate of infection or death in patients with acute pancreatitis at high risk for complications.


This moderate-sized randomized trial won’t change the perceived standard of care, which remains early enteral nutrition in patients with severe acute pancreatitis. It also illustrates the overlap and gray area in differentiating “ordinary” acute pancreatitis (who are advised to get no nutrition) from “severe” (who are supposed to get early enteric tube feedings). PulmCCM



A sneaky extra, personal favourite.

11. Prevalence and impact of frailty on mortality in elderly ICU patients: a prospective, multicenter, observational study.

Intensive Care Med. 2014 May;40(5):674-82. doi: 10.1007/s00134-014-3253-4.

Le Maguet P et al.

PURPOSE: Frailty is a recent concept used for evaluating elderly individuals. Our study determined the prevalence of frailty in intensive care unit (ICU) patients and its impact on the rate of mortality.

CONCLUSIONS: Frailty is a frequent occurrence and is independently associated with increased ICU and 6-month mortalities. Notably, the CFS predicts outcomes more effectively than the commonly used ICU illness scores.

 Shrinking’, weak, slow, easily-tired, minimally active patients do worse than expected from disease severity scores. Not a surprise but this article usefully builds on previous definitions of frailty and emphasises that patients can look very similar on paper (severity scores etc) but frailty is always worth assessing.

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  1. Olusegun Olusanya

    Great work Justin.

    I think the post on Destiny II needs modifying?

  1. LITFL Review 168 - LITFL

    […] Mandeville of ICMWK has released his list of 10ish favourite studies of 2014. It’s a great list (even though he clearly can’t count). […]

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