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Intensive Care Medicine

, Volume 44, Issue 12, pp 2257–2259 | Cite as

Focus on randomised clinical trials

  • Anders PernerEmail author
  • Peter B. Hjortrup
  • Ville Pettilä
Editorial

Introduction

Randomised clinical trials (RCT) are the core of evidence-based medicine (EBM) because their results may inform clinical practice, either directly or after the uptake in systematic reviews and clinical practice guidelines. While the interpretation and translation of RCT results into clinical practice is complex [1, 2], the continued development, conduct and publication of RCTs advances our knowledge and care, even though the majority of trials produce neutral results. Importantly, the trials should have the highest possible internal and external validity to have full impact on clinical practice. In this article, we highlight recent RCTs published in Intensive Care Medicine (ICM). Their results add to what appears to be a constant theme in critical care, ‘less is more’ based on RCT results (Table 1) [3].
Table 1

Randomised clinical trials done in the ICU setting where the results indicated that doing less is as good or better than doing more

Intervention vs. control in the pivotal trial

Interventions that can be used less in the ICU

Lower vs. higher tidal volume in patients with ARDS: the ARMA trial

Less use of higher tidal volumes

Restrictive vs. liberal blood transfusion in general ICU patients with anaemia: the TRICC trial

Less use of blood transfusion

Low dose dopamine vs placebo in ICU patients with SIRS and early renal dysfunction

Less use of dopamine

Albumin vs. saline in general ICU patients: the SAFE trial

Less use of albumin

Strict vs. moderate glycaemic control in general ICU patients: the NICE-SUGAR trial

Less use of strict glycaemic control

HES vs. crystalloid in patients with sepsis: the 6S trial

No more use of HES

Higher- vs. lower-intensity CRRT in ICU patients with AKI: the RENAL trial

Less intensive CRRT

APC vs. placebo in ICU patients with persistent septic shock: the PROWESS shock trial

No more use of APC

Restrictive vs. liberal blood transfusion in ICU patients with septic shock and anaemia: the TRISS trial

Less use of blood transfusion

Targeted temperature management at 33 °C vs 36 °C in unconscious adult survivors of out-of-hospital cardiac arrest: the TTM trial

Less use of cooling to 33 °C

HFOV vs. standard ventilation in patients with moderate-to-severe ARDS: the OSCILLATE trial

Less use of HFOV

Early vs. late parenteral nutrition in ICU patients to supplement insufficient enteral nutrition: the EPANIC trial

Less use of early parenteral nutrition

Permissive underfeeding vs. standard enteral feeding in adult ICU patients: the PERMIT trial

Less use of early enteral nutrition

Pantoprazole vs. placebo in ICU patients at risk of gastrointestinal bleeding: the SUP-ICU trial

Less use of prophylactic pantoprazole

AKI acute kidney injury, APC activated protein C, ARDS acute respiratory distress syndrome, CRRT continuous renal replacement therapy, HES hydroxyethyl starch, HFOV high-frequency oscillatory ventilation, SIRS systemic inflammatory response syndrome

Less is more is a constant theme also in ICM

Several systematic reviews and RCTs published in ICM add to the ‘less in more’ theme in critical care. The use of conservative vs. more liberal fluid strategies, after the initial management of patients with sepsis or ARDS, showed no significant effect on mortality, but reduced time on mechanical ventilation with conservative fluid strategies in meta-analysis of RCTs [4]. Stricter glycaemic control in critically ill patients did not result in improved outcomes as compared to less strict control in two network meta-analyses of RCTs, and the rates of hypoglycaemia were increased with stricter control [5, 6], as was 90-day mortality in the largest trial [7]. Along these lines, an RCT of early goal-directed nutrition vs. standard nutritional care in mechanically ventilated ICU patients resulted in more episodes of severe hyperglycaemia and higher use of insulin, and not in improvements in shorter- or longer-term patient-important outcomes [8]. Statins did not reduce the mortality in patients with ARDS, but increased markers of muscle and liver injury in an individual patient data meta-analysis of six placebo-controlled RCTs [9]. The use of intravenous polyspecific immunoglobulin G did not improve any outcomes in patients with necrotising soft tissue infections in a small single-centre, placebo-controlled RCT [10]. In a small single-centre RCT, the use of biomarkers of candida infection facilitated early discontinuation of empiric antifungal treatment in mixed ICU patients [11]. Meanwhile, the use of molecular detection of pathogens in patients with suspected severe infections resulted in more frequent microbiological diagnosis and appropriate antimicrobial cover [12]. Clearly, the safety of any reductions in antibiotic use based on these two interventions should be tested in large multicentre RCTs with lowest possible risk of bias. On the other hand, delays in the administration of antibiotic and in source control may be associated with worse outcome in patients with septic shock, but a multifaceted educational intervention did not reduce such delays as compared with standard education in a cluster RCT of 40 German hospitals [13].

We also care for patients’ relatives, but RCTs testing interventions aimed at them are rare. This should change because we cannot predict the benefits and harms of interventions given with the best of intentions to improve the well-being of the relatives. In an RCT of relatives to patients who had died in ICU, a condolence letter failed to alleviate grief symptoms and may have worsened depression and PTSD-related symptoms [14].

Do clinical practice guidelines based on RCT results improve care?

Intuitively, the answer to this question would be yes. However, there are data indicating harm from guideline implementation driven by recommendations based on low-quality evidence [15]. The same may have occurred with the initial Surviving Sepsis Campaign (SSC) guideline promoting strict glycaemic control, which was later shown to harm patients [7]. However, guideline groups continue to issue recommendations despite low or very low levels of evidence, as has been the case for the latest iterations of the SSC guideline and those for the management of critical illness-related corticosteroid insufficiency [16, 17]. In both these guidelines, most statements were based on low- or very low-quality evidence, meaning that further research is likely to change the estimates informing these statements. Highlighting the uncertainty in guidelines including the call for more trials on questions with low evidence base may promote the conduct of RCTs in the critical care community and among funders.

Ideally, the implementation of guidelines basing most statements on lower-quality evidence should be tested in trials. This was done in a single-centre RCT in cardiac surgical patients at risk of acute kidney injury (AKI) [18]. The implementation of a care bundle, based on the KDIGO guideline [19], reduced the frequency and severity of AKI after surgery as compared with standard care. These promising results call for more RCTs of guideline implementation. And many more RCTs should be done in the critical care setting in general, given the high degree of uncertainty as shown by the large numbers of recommendations based on low-quality evidence in the clinical practice guideline [16, 17]. If done to the highest standards, RCTs may inform patient care regardless of the results showing benefit, harm or neutral effect of the intervention (Table 1). In any case, it is crucial that the critical care community understands that recommendations based on low-quality evidence may change direction with the evolution of better evidence.

Notes

Compliance with ethical standards

Conflicts of interest

The Dept. of Intensive Care, Rigshospitalet has received support for research from Fresenius Kabi, CSL Behring and Ferring Pharmaceuticals.

References

  1. 1.
    Gattinoni L, Marini JJ, Quintel M (2017) Evidence or belief-based medicine? Ten doubts. Intensive Care Med 43:1392–1394CrossRefPubMedGoogle Scholar
  2. 2.
    Buchman TG, Azoulay E (2017) Practice guidelines as implementation science: the journal editors’ perspective. Intensive Care Med 43:378–379CrossRefPubMedGoogle Scholar
  3. 3.
    Perner A, Gordon AC, Angus DC, Lamontagne F, Machado F, Russell JA, Timsit JF, Marshall JC, Myburgh J, Shankar-Hari M, Singer M (2017) The intensive care medicine research agenda on septic shock. Intensive Care Med 43:1294–1305CrossRefPubMedGoogle Scholar
  4. 4.
    Silversides JA, Major E, Ferguson AJ, Mann EE, McAuley DF, Marshall JC, Blackwood B, Fan E (2017) Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory distress syndrome following the resuscitation phase of critical illness: a systematic review and meta-analysis. Intensive Care Med 43:155–170CrossRefPubMedGoogle Scholar
  5. 5.
    Yamada T, Shojima N, Noma H, Yamauchi T, Kadowaki T (2017) Glycemic control, mortality, and hypoglycemia in critically ill patients: a systematic review and network meta-analysis of randomized controlled trials. Intensive Care Med 43:1–15CrossRefPubMedGoogle Scholar
  6. 6.
    Yatabe T, Inoue S, Sakaguchi M, Egi M (2017) The optimal target for acute glycemic control in critically ill patients: a network meta-analysis. Intensive Care Med 43:16–28CrossRefPubMedGoogle Scholar
  7. 7.
    Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V, Bellomo R, Cook D, Dodek P, Henderson WR, Hebert PC, Heritier S, Heyland DK, McArthur C, McDonald E, Mitchell I, Myburgh JA, Norton R, Potter J, Robinson BG, Ronco JJ (2009) Intensive versus conventional glucose control in critically ill patients. N Engl J Med 360:1283–1297CrossRefGoogle Scholar
  8. 8.
    Allingstrup MJ, Kondrup J, Wiis J, Claudius C, Pedersen UG, Hein-Rasmussen R, Bjerregaard MR, Steensen M, Jensen TH, Lange T, Madsen MB, Moller MH, Perner A (2017) Early goal-directed nutrition versus standard of care in adult intensive care patients: the single-centre, randomised, outcome assessor-blinded EAT-ICU trial. Intensive Care Med 43:1637–1647CrossRefPubMedGoogle Scholar
  9. 9.
    Nagendran M, McAuley DF, Kruger PS, Papazian L, Truwit JD, Laffey JG, Thompson BT, Clarke M, Gordon AC (2017) Statin therapy for acute respiratory distress syndrome: an individual patient data meta-analysis of randomised clinical trials. Intensive Care Med 43:663–671CrossRefPubMedGoogle Scholar
  10. 10.
    Madsen MB, Hjortrup PB, Hansen MB, Lange T, Norrby-Teglund A, Hyldegaard O, Perner A (2017) Immunoglobulin G for patients with necrotising soft tissue infection (INSTINCT): a randomised, blinded, placebo-controlled trial. Intensive Care Med 43:1585–1593CrossRefPubMedGoogle Scholar
  11. 11.
    Rouze A, Loridant S, Poissy J, Dervaux B, Sendid B, Cornu M, Nseir S, group STs (2017) Biomarker-based strategy for early discontinuation of empirical antifungal treatment in critically ill patients: a randomized controlled trial. Intensive Care Med 43:1668–1677CrossRefPubMedGoogle Scholar
  12. 12.
    Cambau E, Durand-Zaleski I, Bretagne S, Brun-Buisson C, Cordonnier C, Duval X, Herwegh S, Pottecher J, Courcol R, Bastuji-Garin S, team Es (2017) Performance and economic evaluation of the molecular detection of pathogens for patients with severe infections: the EVAMICA open-label, cluster-randomised, interventional crossover trial. Intensive Care Med 43:1613–1625CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Bloos F, Ruddel H, Thomas-Ruddel D, Schwarzkopf D, Pausch C, Harbarth S, Schreiber T, Grundling M, Marshall J, Simon P, Levy MM, Weiss M, Weyland A, Gerlach H, Schurholz T, Engel C, Matthaus-Kramer C, Scheer C, Bach F, Riessen R, Poidinger B, Dey K, Weiler N, Meier-Hellmann A, Haberle HH, Wobker G, Kaisers UX, Reinhart K, group Ms (2017) Effect of a multifaceted educational intervention for anti-infectious measures on sepsis mortality: a cluster randomized trial. Intensive Care Med 43:1602–1612CrossRefPubMedGoogle Scholar
  14. 14.
    Kentish-Barnes N, Chevret S, Champigneulle B, Thirion M, Souppart V, Gilbert M, Lesieur O, Renault A, Garrouste-Orgeas M, Argaud L, Venot M, Demoule A, Guisset O, Vinatier I, Troche G, Massot J, Jaber S, Bornstain C, Gaday V, Robert R, Rigaud JP, Cinotti R, Adda M, Thomas F, Calvet L, Galon M, Cohen-Solal Z, Cariou A, Azoulay E, Famirea Study Group (2017) Effect of a condolence letter on grief symptoms among relatives of patients who died in the ICU: a randomized clinical trial. Intensive Care Med 43:473–484CrossRefPubMedGoogle Scholar
  15. 15.
    Kett DH, Cano E, Quartin AA, Mangino JE, Zervos MJ, Peyrani P, Cely CM, Ford KD, Scerpella EG, Ramirez JA (2011) Implementation of guidelines for management of possible multidrug-resistant pneumonia in intensive care: an observational, multicentre cohort study. Lancet Infect Dis 11:181–189CrossRefPubMedGoogle Scholar
  16. 16.
    Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP (2017) Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 43:304–377CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Annane D, Pastores SM, Rochwerg B, Arlt W, Balk RA, Beishuizen A, Briegel J, Carcillo J, Christ-Crain M, Cooper MS, Marik PE, Umberto Meduri G, Olsen KM, Rodgers S, Russell JA, Van den Berghe G (2017) Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Intensive Care Med 43:1751–1763CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Meersch M, Schmidt C, Hoffmeier A, Van Aken H, Wempe C, Gerss J, Zarbock A (2017) Prevention of cardiac surgery-associated AKI by implementing the KDIGO guidelines in high risk patients identified by biomarkers: the PrevAKI randomized controlled trial. Intensive Care Med 43:1551–1561CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Kellum JA, Lameire N (2013) Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1). Crit Care 17:204CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature and ESICM 2018

Authors and Affiliations

  1. 1.Department of Intensive CareRigshospitalet, University of CopenhagenCopenhagenDenmark
  2. 2.Department of Anaesthesia and Intensive CareZealand University HospitalKøgeDenmark
  3. 3.Department of Anesthesiology, Intensive Care and Pain MedicineUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland

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