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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

Introduction

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) (http://www.PICUtrials.net/). 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: http://epicc.mcmaster.ca and http://www.PICUtrials.net/)

Topic area

Subject

Respiratory

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

Bronchiolitis

Cardiovascular

Sodium nitroprusside during prolonged infusion

Dopamine versus epinephrine in septic shock

Hypothermia

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.

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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

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