Intensive Care Medicine

, Volume 42, Issue 8, pp 1203–1205 | Cite as

Focus on paediatrics

  • Mark J. PetersEmail author
  • Warwick Butt
  • Robert C. Tasker
Focus Editorial


There is a staggeringly large gap between the number of patients admitted to the pediatric intensive care unit (PICU) and those enrolled into randomized controlled trials (RCTs)—the currency for acquiring new information for treatment in patient care. The “gap” is a ratio of 100-to-1, i.e., only one patient recruited to an RCT for every 100 patients admitted for PICU care [1]. This “focus on paediatrics” therefore explores how this gap might be closed.

A plea for appropriate outcomes

The recently published unadjusted mortality rate of 26.4 per 1000 PICU admissions [2] in contemporary United States (US) PICU practice questions the legitimacy of mortality as an endpoint for RCTs. It is not relevant to the other 973.6 per 1000 admissions. Pollack et al. [2] addressed this problem by exploring three (or “trichotomous”) outcomes after PICU admission: significant new functional morbidity, intact survival, and death.

Two articles in Intensive Care Medicine (ICM) also question the confidence we might gain from mortality improvements alone. First, Aspesberro et al. [3] reviewed tools for measuring health-related quality of life (HRQL) after PICU admission and concluded that these instruments could be used to assess our 20–50 % rates of morbidity, but the accompanying editorial [4] indicated that more work was needed before qualitative outcomes become the norm in our population. Second, van Zellem et al. [5] showed the expected worse performance in full-scale intelligence quotient (IQ), verbal IQ, and visual memory in 47 survivors of cardiac arrest during childhood. Other, functional domains—executive functioning and visual-motor integration—were relatively intact, and there was often a difference between parent and teacher reports. Therefore, using summary variables for complex conditions, or resorting to parent questionnaire assessments in RCTs may introduce errors in outcomes assessment.

Clinically usable information from observations

Another focus in ICM is large observational studies. Kanthimathinathan et al. [6] undertook a database review of 12,533 PICU admissions and reported unplanned endotracheal tube extubations at a rate of approximately 1 per 2000 intubation days per year.

Comparative effectiveness research (CER) is based on prospective observations that address the question of whether a complex package of care delivery works. The approach examines effectiveness in a homogeneous population (e.g., severe traumatic brain injury) where there is a known difference in outcome and a known difference in care delivery. That is, researchers can measure the difference in outcome and relate these to the package of care and its constituent components. The Approaches and Decisions for Acute Pediatric Traumatic Brain Injury (ADAPT) CER study is currently recruiting patients worldwide. This same approach may be important for complex conditions such as pediatric acute respiratory distress syndrome (pARDS) [7].

Informative clinical experiments: RCTs in critical care

In 2015 there were at least 12 RCTs reported in PICU patients (Table 1) ( Two studies require further comment. The Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) study in 2449 pediatric patients found that using a sedation protocol compared with usual care did not reduce the duration of mechanical ventilation [8]. Of interest, though, 68 % of cases developed “iatrogenic withdrawal”, which means that the future focus should be on this feature as an outcome measure [9]. In ICM, Banupriya et al. [10] demonstrated the superiority of prophylactic probiotics in reducing the incidence of ventilator associated pneumonia (VAP from 39 to 22 per 1000 ventilated days, p = 0.02) in an environment with very high baseline VAP rates. The natural question now is whether this benefit translates to PICUs where the pretest rate of VAP is closer to 4 per 1000 ventilated days.
Table 1

RCTs in pediatric intensive care in 2015 by topic of care (see: and

Topic area



Protocolized sedation versus usual care during mechanical ventilation

Neurally adjusted ventilator assist

Inhaled nitric oxide

Post-endotracheal tube extubation care

Lung inflammation

Ventilator associated pneumonia



Sodium nitroprusside during prolonged infusion

Dopamine versus epinephrine in septic shock


Out-of-hospital cardiac arrest

Severe traumatic brain injury

New methodologies for enhancing patient recruitment to RCTs

The recently published Impregnated central venous CATheters for prevention of bloodstream infection in CHildren (CATCH) trial compared standard with heparin or antibiotic-coated central venous lines (CVL) [11]. There was a small benefit of antibiotic-coated CVLs with respect to bloodstream infections. Of more interest, however, is the use of so-called deferred consent in the research report, which is worthy of further discussion.

In the UK the term “research without prior consent” is preferred to “deferred consent”. In US regulations, the term “waiver or alteration of informed consent” rather than the term “deferred consent” is used because the latter fails to describe the lack of opportunity to avoid or prevent a subject from receiving the intervention under investigation. To date, there have been a number of reports about this approach and we need to gain more insight from PICU families about the potential for this practice. For example, the CATCH trial was the first pediatric critical care RCT to use this approach since UK legislation changed in 2008. In the CONsent methods in childreN’s emergEncy medicine and urgent Care Trials (CONNECT) study, a cohort of parents of children recruited into the CATCH study were interviewed [12]. The investigators found that parents supported research without prior consent and appreciated the reasons for using it as long as their child’s safety was not compromised. However, these parents would be concerned about not seeking prior consent in trials involving either “new” drug interventions or other potentially significant changes in clinical practice. Last, a report from a European group of pediatric clinical researchers described a new framework for informed consent processes under different time constraints [13], which will be applicable to PICU studies.

Moving the field forward and future RCTs

There appear to the three areas that interest our authors in regard to future plans for RCTs. First, corticosteroids in pARDS may be one target [7, 14], but Yehya et al. [15] found that corticosteroid exposure for other indications was widespread in the PICU. However, recruitment to RCTs may be improved by using pulse oximetry to fractional inspired oxygen ratio as an index of severity [16]. Second, intravenous fluid resuscitation and responsiveness [17, 18]; and there may soon be data from the Canadian SQUEEZE (septic shock reversal is quicker in pediatric patients randomized to an early goal directed fluid-sparing strategy versus usual care) and the UK FiSh (Fluids in Shock) studies [19]. Last, non-invasive ventilation [20]; and their may soon be data from the FIRST-line Support for Assistance in Breathing in Children (FIRST-ABC) feasibility study.


  1. 1.
    Tasker RC (2016) Opportunities for enhancing patient recruitment in clinical research: building an evidence base for critical care medicine. Pediatr Crit Care Med 17:267–269CrossRefPubMedGoogle Scholar
  2. 2.
    Pollack MM, Holubkov R, Funai T et al (2015) Simultaneous prediction of new morbidity, mortality, and survival without new morbidity from pediatric intensive care: a new paradigm for outcomes assessment. Crit Care Med 43:1699–1709CrossRefPubMedGoogle Scholar
  3. 3.
    Aspesberro F, Mangione-Smith R, Zimmerman JJ (2015) Health-related quality of life following pediatric critical illness. Intensive Care Med 41:1235–1246CrossRefPubMedGoogle Scholar
  4. 4.
    Agbeko RS, Burns JP, Peters MJ (2015) Tools for revealing uncomfortable truths? Measuring child-centred health-related quality of life after paediatric intensive care. Intensive Care Med 41:1330–1332CrossRefPubMedGoogle Scholar
  5. 5.
    van Zellem L, Buysse C, Madderom M et al (2015) Long-term neuropsychological outcomes in children and adolescents after cardiac arrest. Intensive Care Med 41:1057–1066CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Kanthimathinathan HK, Durward A, Nyman A, Murdoch IA, Tibby SM (2015) Unplanned extubation in a paediatric intensive care unit: prospective cohort study. Intensive Care Med 41:1299–1306CrossRefPubMedGoogle Scholar
  7. 7.
    Peters MJ, Ray S, Kneyber M (2015) Corticosteroids for paediatric ARDS: unjustified—even unjustifiable? Intensive Care Med 41:1685–1687CrossRefPubMedGoogle Scholar
  8. 8.
    Curley MA, Wypij D, Watson RS et al (2015) Protocolized sedation vs usual care in pediatric patients mechanically ventilated for acute respiratory failure: a randomized clinical trial. JAMA 313:379–389CrossRefPubMedGoogle Scholar
  9. 9.
    Tasker RC, Menon DK (2016) Critical care and the brain. JAMA 315:749–750CrossRefPubMedGoogle Scholar
  10. 10.
    Banupriya B, Biswal N, Srinivasaraghavan R, Narayanan P, Mandal J (2015) Probiotic prophylaxis to prevent ventilator associated pneumonia (VAP) in children on mechanical ventilation: an open-label randomized controlled trial. Intensive Care Med 41:677–685CrossRefPubMedGoogle Scholar
  11. 11.
    Gilbert RE, Mok Q, Dwan K et al (2016) Impregnated central venous catheters for prevention of bloodstream infection in children (the CATCH trial): a randomised controlled trial. Lancet 387:1732–1742CrossRefPubMedGoogle Scholar
  12. 12.
    Woolfall K, Frith L, Gamble C et al (2015) How parents and practitioners experience research without prior consent (deferred consent) for emergency research involving children with life threatening conditions: a mixed method study. BMJ Open 5:e008522CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Jansen-van der Weide MC, Caldwell PH, Young B et al (2015) Clinical trial decisions in difficult circumstances: parental consent under time pressure. Pediatrics 136:e983–e992CrossRefPubMedGoogle Scholar
  14. 14.
    Schwingshackl A, Meduri GU, Kimura D, Cormier SA, Anand KJ (2015) Corticosteroids in pediatric ARDS: all cards on the table. Intensive Care Med 41:2036–2037CrossRefPubMedGoogle Scholar
  15. 15.
    Yehya N, Servaes S, Thomas NJ, Nadkarni VM, Srinivasan V (2015) Corticosteroid exposure in pediatric acute respiratory distress syndrome. Intensive Care Med 41:1658–1666CrossRefPubMedGoogle Scholar
  16. 16.
    Khemani RG, Rubin S, Belani S et al (2015) Pulse oximetry vs. PaO2 metrics in mechanically ventilated children: Berlin definition of ARDS and mortality risk. Intensive Care Med 41:94–102CrossRefPubMedGoogle Scholar
  17. 17.
    Bhaskar P, Dhar AV, Thompson M, Quigley R, Modem V (2015) Early fluid accumulation in children with shock and ICU mortality: a matched case control study. Intensive Care Med 41:1445–1453CrossRefPubMedGoogle Scholar
  18. 18.
    Saxena R, Durward A, Steeley S, Murdoch IA, Tibby SM (2015) Predicting fluid responsiveness in 100 critically ill children: the effect of baseline contractility. Intensive Care Med 41:2161–2169CrossRefPubMedGoogle Scholar
  19. 19.
    Inwald DP, Butt W, Tasker RC (2015) Fluid resuscitation of shock in children: what, whence and whither? Intensive Care Med 41:1457–1459CrossRefPubMedGoogle Scholar
  20. 20.
    Bakalli I, Celaj E, Simaku A, Kola E, Sallabanda S (2015) Predictors of noninvasive ventilation success in children with acute respiratory failure. Intensive Care Med 41:950–951CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg and ESICM 2016

Authors and Affiliations

  • Mark J. Peters
    • 1
    • 2
    Email author
  • Warwick Butt
    • 3
    • 4
    • 5
  • Robert C. Tasker
    • 6
    • 7
  1. 1.Paediatric Intensive Care UnitGreat Ormond St Hospital for Children NHS Foundation TrustLondonUK
  2. 2.Respiratory Critical Care and Anaesthesia UnitInstitute of Child Health, University College LondonLondonUK
  3. 3.Intensive Care UnitRoyal Childrens HospitalMelbourneAustralia
  4. 4.Murdoch Childrens Research InstituteMelbourneAustralia
  5. 5.Department of PaediatricsUniversity of MelbourneParkvilleAustralia
  6. 6.Department of Anesthesia, Perioperative and Pain Medicine, Division of Critical Care MedicineBoston Children’s Hospital and Harvard Medical SchoolBostonUSA
  7. 7.Department of NeurologyBoston Children’s Hospital and Harvard Medical SchoolBostonUSA

Personalised recommendations