Advertisement

Intensive Care Medicine

, Volume 45, Issue 12, pp 1806–1809 | Cite as

Less is more in critical care is supported by evidence-based medicine

  • Catherine L. AuriemmaEmail author
  • Greet Van den Berghe
  • Scott D. Halpern
Less is more in Intensive Care

The notion that “less is (or may be) more” in intensive care medicine has been contemplated by experts for decades. However, not until Kox and Pickkers’ review in 2013 had there been careful consideration of the evidence supporting this theory [1]. Their thought-provoking article focused specifically on sepsis, but the intervening years have yielded expanded evidence supporting this notion across many critical conditions. As healthcare systems seek to incentivize high-value care, transparency, and adherence to evidence-based practice guidelines, we must assess the strength of the evidence base regarding less is more. Here, we discuss recent randomized clinical trials (RCTs) that support the notion that even in intensive care units (ICUs), less intensive interventions may prove superior.

Protocolized ICU care

Perhaps the biggest giant to fall in the last six years is early-goal-directed therapy (EGDT) for sepsis care—or at least the variety of EGDT proposed by Rivers and colleagues [2]. Three separate RCTs conducted across seven countries have shown no mortality benefit to protocolized EGDT when compared to protocol-based standard therapy or usual care [3, 4, 5]. In all studies, patients in the EGDT group received increased days of vasopressor support. Mouncey et al. additionally found that EGDT was associated with increased ICU length of stay (LOS) and costs [4]. While these studies have not debunked the value of early antibiotics and resuscitation, they have been practice-changing around the more invasive components of the original EGDT protocol, specifically the routine use of central venous catheters and using central venous saturations to guide blood transfusion.

A further challenge to increasingly protocolized ICU care came from Mehta and colleagues, who found that the addition of daily sedation interruptions to protocolized sedation in mechanically ventilated patients did not reduce duration of mechanical ventilation or ICU stay [6]. While clinical outcomes were similar across groups, the addition of sedation interruption was associated with greater nursing workload.

Ventilatory support

A paradigmatic example of a less-is-more strategy is the use of low tidal volume ventilation. In the two decades following the landmark ARMA trial [7], additional evidence supports simplified versions of low tidal volume strategies for patients with ARDS over more complex and aggressive strategies. The addition of lung recruitment maneuvers and PEEP titration increased mortality when compared to low-PEEP strategy in patients with moderate to severe ARDS [8]. The aggressive ventilator strategy also decreased mean ventilator-free days (VFDs) and increased risk of pneumothorax and barotrauma.

Resuscitation fluids and transfusions

Several RCTs have also compared the administration of colloid with crystalloid solutions. In patients with severe sepsis, fluid resuscitation with hydroxyethyl starch (HES) was compared to Ringer’s acetate. The trial found an increased risk of death and renal-replacement therapy (RRT) in patients randomized to the HES group [9]. In a second trial, resuscitation with HES was compared to normal saline solution in a mixed ICU population [10]. While mortality did not differ across arms, again, increased rates of RRT were noted in the HES group.

Another key example of a less-is-more approach is the guidance, since the original TRICC trial, to use a restrictive rather than liberal threshold for transfusing red blood cells [11]. Recent evidence solidified the less-is-more approach regarding transfusion in populations initially excluded from early trials [11, 12]. An RCT of patients with severe acute upper gastrointestinal bleeding revealed improved survival, reduced bleeding, and fewer adverse events with a restrictive transfusion approach [13]. Another RCT among patients undergoing cardiac surgery revealed the restrictive approach was generally no worse than the liberal approach despite significantly reduced transfusions, and was superior to the liberal approach among older patients [14].

Renal replacement therapy

Gaudry et al. completed a multicenter RCT of patients with severe acute kidney injury without emergent indications for dialysis to receiving renal replacement therapy (RRT) either early (immediately after randomization) or delayed (only if and when a severe complication of renal failure developed) [15]. While there was no difference in mortality between groups, the delayed strategy enabled the avoidance of RRT in 61% of survivors.

Blood pressure goals

In patients with septic shock, Asfar et al. compared a higher target of mean arterial blood pressure (80–85 mmHg) to the more traditional 65–70 mmHg [16]. The more aggressive blood pressure target had no benefit on mortality. In a sub-group of patients with baseline chronic hypertension, the higher blood pressure target was associated with decreased need for RRT without corresponding improvements in mortality. While major adverse events were similar across groups, there were higher rates of new atrial fibrillation in the high-target group. Larger, ongoing RCTs comparing various high vs low blood pressure targets in the ICU will soon shed further light on this common dilemma.

Nutrition

Caloric intake seems like an area in which more should simply be more given the adverse consequences of malnutrition among the critically ill. Yet again, more aggressive strategies have not proven beneficial. Delaying initiation of parenteral nutrition to supplement caloric intake of both adult and pediatric patients not meeting their goals enterally was associated with many benefits including shorter LOS, fewer ICU infections, and decreased cost of care [17, 18]. In a trial of energy-dense vs routine enteral nutrition in mechanically ventilated patients, the more intense strategy did not show a mortality benefit, but did result in more gastrointestinal intolerance and hyperglycemia [19]. These results were similar to those seen in an earlier RCT comparing trophic enteral feeding with full dose feeding [20].

Conclusions and future directions

Together, these RCTs support the notion that less intensive management is often superior to more intensive approaches to critical care delivery. Though many of the trials were null with regard to mortality, most ICU trials lack adequate statistical power to identify plausible mortality differences [21]. Importantly, as designed, the trials above frequently demonstrate that secondary outcomes favor the less intensive approach and establish real harm associated with more intensive interventions. Statistical power is not the only limitation in many of these trials (Table 1). Development of a more personalized approach, or the design of trials with better predictive and prognostic enrichment may allow for a more nuanced understanding of when and for whom “more is more” [22, 23]. However, with currently available evidence, the uniform absence of benefits to more intensive approaches itself favors a less intensive approach—why would one use more costly strategies when less costly ones are at least as good?
Table 1

Randomized clinical trials demonstrating that “less is more”

Intervention

Effect

Protocolized ICU care

 Protocol based EGDT vs protocol-based standard therapy vs usual care [3, 4, 5]

No mortality benefit [3, 4, 5]

EGDT associated with: longer ICU LOS [4]

Increased days on cardiovascular support [3, 4, 5]

Increased costs [4]

 Protocol sedation plus daily sedation interruption vs standard protocol sedation [6]

No mortality benefit

Increased nursing workload

Ventilatory support

 Lung recruitment and PEEP titration vs low PEEP [8]

Increased mortality

Decreased mean ventilator-free days

Increased risk of pneumothorax Increased barotrauma

Resuscitation fluids and transfusions

 Hydroxyethyl starch vs Ringers acetate [9] or normal saline [10]

Increased mortality [9]

Increased need for RRT [9, 10]

 Restrictive (hemoglobin of 7 g per deciliter) vs liberal (hemoglobin of 9 g per deciliter) red blood cell transfusion for acute UGIB [13]

Improved survival

Decreased adverse events in restrictive strategy

Renal replacement therapy

 Early vs delayed initiation of continuous RRT in patients with AKI [15]

No benefit, avoidance of RRT 49% of patients in the delayed arm

Blood pressure goals

 MAP targets of 80–85 mmHg vs 60–70 mmHg [16]

No mortality benefit

Increased new atrial fibrillation in high-target group

Less RRT in sub-group of patients with chronic hypertension in the high-target group

Nutrition

 Early (within 48 h) vs late parenteral nutrition to supplement enteral nutrition [17, 18]

No mortality benefit

Late initiation associated with:

Shorter ICU and hospital LOS

Fewer ICU infections

Fewer days of RRT

Decreased cost

 Energy-dense vs routine enteral nutrition in mechanically ventilated patients [19]

No difference in mortality

Increased upper gastrointestinal intolerance and hyperglycemia

 Trophic vs full enteral feeding for the first 6 days of mechanical ventilation [20]

No difference in mortality or VFDs

Increased vomiting, constipation, and need for insulin in full feeding group

AKI acute kidney injury, EGDT early-goal directed therapy, LOS length of stay, MAP mean arterial pressure, PEEP positive end-expiratory pressure, RRT renal replacement therapy, TEN total enteral nutrition, UGIB upper gastrointestinal bleed, VFDs ventilator-free-days

Notes

Funding

Dr. Van den Berghe holds an ERC Advanced Grant (AdvG-2017-785809) from Horizon 2020 Program of the EU and receives long-term structural funding by the Methusalem Program funded by the Flemish Government (METH/14/06).

Compliance with ethical standards

Conflicts of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

References

  1. 1.
    Kox M, Pickkers P (2013) “Less is more” in critically ill patients not too intensive. JAMA Intern Med 173:1369–1372.  https://doi.org/10.1001/jamainternmed.2013.6702 CrossRefPubMedGoogle Scholar
  2. 2.
    Rivers E, Nguyen B, Havstad S et al (2001) Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 345:1368–1377.  https://doi.org/10.1056/NEJMoa010307 CrossRefPubMedGoogle Scholar
  3. 3.
    ARISE Investigators and the ANZICS Clinical Trials Group (2014) Goal-directed resuscitation for patients with early septic shock. N Engl J Med 371:1496–1506.  https://doi.org/10.1056/nejmoa1404380 CrossRefGoogle Scholar
  4. 4.
    Mouncey PR, Power GS, Harrison DA et al (2015) Trial of early, goal-directed resuscitation for septic shock. N Engl J Med 372:1301–1311.  https://doi.org/10.1056/NEJMoa1500896 CrossRefPubMedGoogle Scholar
  5. 5.
    Quinlan M (2014) A randomized trial of protocol-based care for early septic shock. J Emerg Med 47:256–257.  https://doi.org/10.1016/j.jemermed.2014.06.009 CrossRefGoogle Scholar
  6. 6.
    Mehta S, Burry L, Cook D et al (2012) Daily sedation interruption in mechanically ventilated critically ill patients cared for with a sedation protocol: a randomized controlled trial. JAMA 308:1985–1992.  https://doi.org/10.1001/jama.2012.13872 CrossRefPubMedGoogle Scholar
  7. 7.
    The Acute Respiratory Distress Syndrome Network (2000) Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury. N Engl J Med 342:1301–1308.  https://doi.org/10.1056/NEJM200009143431113 CrossRefGoogle Scholar
  8. 8.
    Cavalcanti AB, Suzumura ÉA, Laranjeira LN et al (2017) Effect of lung recruitment and titrated positive end-expiratory pressure (PEEP) vs low PEEP on mortality in patients with acute respiratory distress syndrome—a randomized clinical trial. JAMA 318:1335–1345.  https://doi.org/10.1001/jama.2017.14171 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Åneman A et al (2012) Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med 367:124–134.  https://doi.org/10.1177/175114371301400116 CrossRefPubMedGoogle Scholar
  10. 10.
    Myburgh JA, Finfer S, Bellomo R et al (2012) Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 367:1901–1911.  https://doi.org/10.1056/nejmoa1209759 CrossRefPubMedGoogle Scholar
  11. 11.
    Hébert PC, Wells G, Blajchman MA et al (1999) A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 340:409–417CrossRefGoogle Scholar
  12. 12.
    Lacroix J, Hébert PC, Hutchison JS et al (2007) Transfusion strategies for patients in pediatric intensive care units. N Engl J Med 356:1609–1619CrossRefGoogle Scholar
  13. 13.
    Villanueva C, Colomo A, Bosch A et al (2013) Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med 368:11–21.  https://doi.org/10.1056/NEJMoa1211801 CrossRefPubMedGoogle Scholar
  14. 14.
    Mazer CD, Whitlock RP, Fergusson DA et al (2017) Restrictive or liberal red-cell transfusion for cardiac surgery. N Engl J Med 377:2133–2144.  https://doi.org/10.1056/nejmoa1711818 CrossRefPubMedGoogle Scholar
  15. 15.
    Gaudry S, Hajage D, Schortgen F et al (2016) Initiation strategies for renal-replacement therapy in the intensive care unit. N Engl J Med 375:122–133.  https://doi.org/10.1056/nejmoa1603017 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Asfar P, Meziani F, Hamel J-F et al (2014) High versus low blood-pressure target in patients with septic shock. N Engl J Med 370:1583–1593.  https://doi.org/10.1056/NEJMoa1312173 CrossRefPubMedGoogle Scholar
  17. 17.
    Casaer MP, Mesotten D, Hermans G et al (2011) Early versus late parenteral nutrition in critically ill adults. N Engl J Med 365:506–517.  https://doi.org/10.1056/NEJMoa1102662 CrossRefPubMedGoogle Scholar
  18. 18.
    Fivez T, Kerklaan D, Mesotten D et al (2016) Early versus late parenteral nutrition in critically ill children. N Engl J Med 374:1111–1122.  https://doi.org/10.1056/NEJMoa1514762 CrossRefPubMedGoogle Scholar
  19. 19.
    TARGET Investigators for the ANZICS Clinical Trials Group, Chapman M, Peake SL et al (2018) Energy-dense versus routine enteral nutrition in the critically ill. N Engl J Med 379:1823–1834.  https://doi.org/10.1056/NEJMoa1811687 CrossRefGoogle Scholar
  20. 20.
    National Heart Lung and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Rice TW, Wheeler AP et al (2012) Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA 307:795–803.  https://doi.org/10.1001/jama.2012.137 CrossRefGoogle Scholar
  21. 21.
    Harhay MO, Wagner J, Ratcliffe SJ et al (2014) Outcomes and statistical power in adult critical care randomized trials. Am J Respir Crit Care Med 189:1469–1478.  https://doi.org/10.1164/rccm.201401-0056CP CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Prescott HC, Calfee CS, Taylor Thompson B et al (2016) Toward smarter lumping and smarter splitting: rethinking strategies for sepsis and acute respiratory distress syndrome clinical trial design. Am J Respir Crit Care Med 194:147–155.  https://doi.org/10.1164/rccm.201512-2544CP CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Laffey JG, Kavanagh BP (2018) Negative trials in critical care: why most research is probably wrong. Lancet Respir Med 6:659–660CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Pulmonary, Allergy, and Critical Care Medicine, Department of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Palliative and Advanced Illness Research (PAIR) Center at the University of PennsylvaniaPhiladelphiaUSA
  3. 3.Leonard Davis Institute of Health EconomicsUniversity of PennsylvaniaPhiladelphiaUSA
  4. 4.Clinical Division and Laboratory of Intensive Care MedicineKU LeuvenLouvainBelgium
  5. 5.Department of Biostatistics, Epidemiology, and InformaticsUniversity of PennsylvaniaPhiladelphiaUSA
  6. 6.Department of Medical Ethics and Health PolicyUniversity of PennsylvaniaPhiladelphiaUSA

Personalised recommendations