The intensive care medicine clinical research agenda in paediatrics

Abstract

Background
Intensive Care Medicine set us the task of outlining a global clinical research agenda for paediatric intensive care (PIC). In line with the clinical focus of this journal, we have limited this to research that may directly influence patient care. Methods
Clinician researchers from PIC research networks of varying degrees of formality from around the world were invited to answer two main questions: (1) What have been the major recent advances in paediatric critical care research? (2) What are the top 10 studies for the next 10 years? Results(1) Inclusive databases are well established in many countries. These registries allow detailed observational studies and feasibility testing of clinical trial protocols. Recent trials are larger and more valuable, and (2) most common interventions in PIC are not evidenced-based. Clinical studies for the next 10 years should address this deficit, including: ventilation techniques and interfaces; fluid, transfusion and feeding strategies; optimal targets for vital signs; multiple organ failure definitions, mechanisms and treatments; trauma, prevention and treatment; improving safety; comfort of the patient and their family; appropriate care in the face of medical complexity; defining post-PICU outcomes; and improving knowledge generation and adoption, with novel trial design and implementation strategies. The group specifically highlighted the need for research in resource-limited environments wherein mortality remains often tenfold higher than in well-resourced settings. Conclusion
Paediatric intensive care research has never been healthier, but many gaps in knowledge remain. We need to close these urgently. The impact of new knowledge will be greatest in resource-limited environments.

Full text

Intensive Care Med
DOI 10.1007/s00134-017-4729-9
RESEARCH AGENDA
The intensive care medicine clinical
research agenda inpaediatrics
Mark J. Peters1 , Andrew Argent2, Marino Festa3, Stéphane Leteurtre4, Jefferson Piva5, Ann Thompson6,
Douglas Willson7, Pierre Tissières8, Marisa Tucci9,10 and Jacques Lacroix10*
© 2017 Springer-Verlag Berlin Heidelberg and ESICM
Abstract
Background: Intensive Care Medicine set us the task of outlining a global clinical research agenda for paediatric inten-
sive care (PIC). In line with the clinical focus of this journal, we have limited this to research that may directly influence
patient care.
Methods: Clinician researchers from PIC research networks of varying degrees of formality from around the world
were invited to answer two main questions: (1) What have been the major recent advances in paediatric critical care
research? (2) What are the top 10 studies for the next 10 years?
Results: (1) Inclusive databases are well established in many countries. These registries allow detailed observational
studies and feasibility testing of clinical trial protocols. Recent trials are larger and more valuable, and (2) most com-
mon interventions in PIC are not evidenced-based. Clinical studies for the next 10 years should address this deficit,
including: ventilation techniques and interfaces; fluid, transfusion and feeding strategies; optimal targets for vital
signs; multiple organ failure definitions, mechanisms and treatments; trauma, prevention and treatment; improving
safety; comfort of the patient and their family; appropriate care in the face of medical complexity; defining post-PICU
outcomes; and improving knowledge generation and adoption, with novel trial design and implementation strate-
gies. The group specifically highlighted the need for research in resource-limited environments wherein mortality
remains often tenfold higher than in well-resourced settings.
Conclusion: Paediatric intensive care research has never been healthier, but many gaps in knowledge remain. We
need to close these urgently. The impact of new knowledge will be greatest in resource-limited environments.
Keywords: Children, Critical care, Intensive care, Paediatrics, Research
Introduction
Research in critically ill patients is difficult; research in
critically ill children even more so. Some of this chal-
lenge arises from our patients. ey are heterogeneous
across age ranges and comorbidities, suffer from poorly
defined clinical syndromes—just what are sepsis or mul-
tiple organ dysfunction syndrome (MODS) exactly?—
exhibit rapidly changing physiology—when deteriorating
or recovering—but still have a low mortality. Further
challenges arise from our personalities as paediatric
intensivists. e ‘doubt everything’ mantra of the scien-
tist perhaps clashes with the need for clear thinking and
communication in a clinical crisis. Nicholson [1] wrote
that “paediatric intensivists are not strong believers in
the scientific method” and Zimmerman [2] describes
that we prefer to make empirical decisions inferred from
known physiology, saying that paediatric intensivists are
“inclined to action rather than deliberate investigation.”
Moreover, health problems, disease processes and out-
comes may be very different in countries with different
*Correspondence: Jacques_lacroix@ssss.gouv.qc.ca
10 Division of Pediatric Intensive Care Medicine, Department of Pediatrics,
CHU Sainte-Justine, Université de Montréal, Sainte-Justine Hospital, Room
3431, 3175 Côte Sainte-Catherine, Montreal, QC H3T 1C5, Canada
Full author information is available at the end of the article

diseases epidemiology and with different wealth and
resources.
is is perhaps true, both in the moment of choosing
therapies at the bedside and also in planning careers.
e problem is not lack of interest in most instances, but
rather overwhelming clinical demands or low propen-
sity of granting agencies to finance paediatric studies.
e result is that there are relatively few academics in
paediatric intensive care. More importantly, most of our
practice is not supported by high-quality evidence. Even
very commonly used interventions such as ventilation,
cardiovascular support, sedation, transfusion, fluids and
nutrition vary widely between units and individual inten-
sivists. is uncomfortable truth has remained largely
unobserved because our headline outcome—survival to
discharge—continues to improve (from ~80 to 90% in
the 1980s to >97% in 2013 in developed countries) [1, 3,
4]. Currently, fewer than 1 in 100 admissions in paediat-
ric intensive care units (PICU) globally are recruited in
clinical trials; contrasts have been drawn to the tenfold
greater number of clinical trials completed in adult criti-
cal care [5].
e Canadian Paediatric Society (CPS) wrote: “Health
research is a moral duty because it is the foundation for
evidence-based care by all health care practitioners” [6].
Research is not an easy task and is encumbered by many
obstacles. Clinical research is more difficult in children
because it “poses important challenges with regard to
informed consent and assent, vulnerability and potential
conflicts of interest” [6]. In spite of this, research should
flourish in PICU. We have higher levels of staffing and
much greater resolution of physiological monitoring data
and clinical records than other areas. ere is no short-
age of patients, many of whom receive similar interven-
tions for organ support, and there is a huge potential for
lifelong clinical and cost-effective consequences of our
care. e scarcity of existing data means that each new
study is welcomed and valued.
So where should we be aiming? Should we really target
the ‘research as a standard of care’ [2] approach of itera-
tive randomised controlled trials (RCT) that have trans-
formed the outcomes for acute leukaemia? We would say
that this suggestion no longer seems fanciful. Data col-
lection on paediatric critical illness is increasingly formal
and standardised. Several research groups in many coun-
tries (United Kingdom, United States, Australia and New
Zealand, Netherlands, Canada, Italy, etc.) have registries
providing case-mix adjusted outcomes data. Submissions
to some of these like UK PICANet or ANZICS CORE
are mandated for funding for PICU services; others are
financed by grants and/or private funds, like Virtual
PICU (vPICU) (http://www.chla.org/virtual-picu) in the
United States and large research programs conducted by
members of the Pediatric Acute Lung Injury and Sepsis
Investigators (PALISI) Network (http://www.palisi.org)
and of the Canadian Critical Care Trials Group (http://
www.ccctg.ca). ese comprehensive databases allow
monitoring of performance, planning of service devel-
opment, and, most importantly from the scope of this
review, informing on the feasibility of testable specific
hypothesis with clinical trials.
ings are changing. e web site http://picutrials.
net records RCTs in paediatric intensive care; there
have been 337 RCTs published since 1984. While that
may seem disappointing, 9% of these were published
in 2015. Yes, most are still single-centre studies with
50–150 recruits, but there are an increasing number of
collaborative, large multiple-centre RCTs undertaken by
research collaborations of various degrees of formality
(Table1).
Some funding bodies—such as the National Institute
of Health Research in the UK—have shifted some of the
focus away from laboratory based basic science research
towards pragmatic, real-world clinical questions often
addressing best use of existing therapies. is may be
part of a wider realisation that, to date at least, genomic
and stem cell/regenerative medicine advances in many
fields have not delivered the anticipated clinical impact.
Joyner and colleagues argued in a recent JAMA viewpoint
that progress has been inhibited by adherence to this nar-
rative [7]. Readers are likely to have a range of views on
this position, but we can probably agree that if there is a
continued move towards pragmatic clinical investigation,
then paediatric intensivists are especially well positioned
to respond.
Intensive care medicine sets us the task of outlining a
global clinical research agenda for paediatric intensive
care. is might at first sight appear to be an impossibly
difficult request given the diversity of healthcare systems,
resources and case-mix. But given the progress develop-
ing collaborations mentioned above and perhaps a new
recognition of the value of pragmatic research, this might
be an opportunity to set our agenda for the next 10years.
e authors here represent a convenience sample of pae-
diatric critical care collaborations, networks or societies
from five continents with significant research outputs.
is is not a definitive list. We took the decision to focus
on patient-oriented clinical investigator-led research.
e purpose of this article is to reflect on what has been
achieved and suggest what might be research priorities
for our field globally. We are not aware of previous simi-
lar attempts to do this outside North America. Any com-
mon ground in priorities and potential for collaboration
should be celebrated as an opportunity for more efficient
and timely research that increases the potential for gen-
eralisability of any results (Fig.1).

What have been the major recent advances inthe
eld?
Large databases
Even though there are data to show that there is massive
variation in care between units, which may create prob-
lems with the understanding of the overall data, formal
inclusive large databases systematically recording case-
mix-adjusted outcomes have helped us to understand
our practice and have provided feasibility data for ran-
domised trials. Table2 shows examples of large datasets
(≥1500 cases) from collaborative registries and their
conclusions.
Recognition ofthe high morbidity followingPICU
admission
In wealthier countries, mortality is no longer the only
important outcome from paediatric critical illness. As
death before PICU discharge becomes an increasingly
rare event (2–6% in many high-resource settings), Pollack
and colleagues suggested the need for describing three
outcomes: intact survival, new functional morbidity and
death [4]. Aspesberro and colleagues [8] confirmed new
morbidity in 2–50% of PICU survivors and compared
tools that are now available (PedsQL 4.0 Generic Core
Scales, KIDSCR-27, CHQ-PF28 and KINDL) for estimat-
ing health-related quality of life in children. Similar many
investigators have uncovered a high level of previously
unappreciated morbidity in survivors of surgery for con-
genital cardiac disease and intensive care [4, 9].
More conservative use ofsupportive treatments
A feature of the findings from well-constructed trials is
that they tend to favour (or at least show no harm from)
less aggressive care. is pattern can be seen in non-
invasive ventilation [10], transfusion thresholds [11, 12],
hypothermia for traumatic brain injury [13], glycaemic
control [14], and timing of parenteral nutrition [15].
Completion ofstudies inemergency care scenarios
In the last few years, we have seen some notable examples
of RCTs in challenging time-critical scenarios—some-
thing relatively rare in our field previously [16]. Ventura
etal. [17] in San Paolo studied 120 children with septic
shock randomised to epinephrine versus dopamine as the
first-line vasoactive drug. ey described epinephrine as
superior in a case-mix-adjusted model (odds ratio 6.5;
95% CI 1.1–37.8; p=0.037).
e erapeutic Hypothermia After Pediatric Cardiac
Arrest (THAPCA) investigators published two important
RCTs: the erapeutic Hypothermia After Out-of-Hospi-
tal Cardiac Arrest [18] and the erapeutic Hypothermia
After In-Hospital Cardiac Arrest [19]; both trials showed
no advantage of hypothermia (33.0 °C) over active
Table 1 Multiple-centre randomised controlled trials recruiting more than1000 critically ill children
PALISI paediatric acute lung injury and sepsis investigators, PICS-SG Pediatric Intensive Care Society Study Group
Research network/collaborative group/registry/data‑
base Study title Participants Findings
No group [15] Early vs. late parenteral nutrition in critically ill children 1440 In critically ill children, withholding parenteral nutrition for
1 week in the ICU was clinically superior to providing early
parenteral nutrition
PICS-SG: CATCH trial investigators [21] Impregnated central venous catheters for prevention of
bloodstream infection in children (the CATCH trial): a
randomised controlled trial
1485 Antibiotic-impregnated central venous catheters significantly
reduced the risk of blood stream infections compared to
standard and heparin central venous catheters
PICS-SG CHiP Investigators [14] A randomised trial of hyperglycaemic control in pediatric
intensive care 1369 Tight glycaemic control in critically ill children had no
significant effect on major clinical outcomes, although the
incidence of hypoglycaemia was higher with tight glucose
control than with conventional glucose control
Pediatric SCRUB Trial Study Group [76] Daily chlorhexidine bathing to reduce bacteraemia in
critically ill children: a multicentre, cluster-randomised,
crossover trial
4947 Critically ill children receiving daily chlorhexidine bathing
had a lower incidence of bacteraemia compared with
those receiving a standard bathing routine
PALISI network [60] Protocolised sedation vs. usual care in pediatric patients
mechanically ventilated for acute respiratory failure: a
randomised clinical trial (RESTORE)
2449 Among children undergoing mechanical ventilation for
acute respiratory failure, the use of a sedation protocol
compared with usual care did not reduce the duration of
mechanical ventilation

avoidance of fever (36.8°C). ese studies are remark-
able achievements especially given that they used prior
informed consent with the complexities of achieving this
in such pressured scenarios.
Development andvalidation ofconsent models suitable
foremergency care inchildren
Alterative approaches to consent in emergency situations
and new research about their acceptability are poten-
tially important developments. e use of a ‘deferred’
or ‘delayed’ consent process (or more correctly ‘research
without prior consent’) has been studied by Woolfall and
colleagues who produced the Connect guidance [20].
Work with parents and families in the UK participating
in the catheter-associated infections in children trial [21],
and more recently in the Fluid Expansion As Supportive
erapy feasibility studies (ISRCTN15244462) suggest a
very reassuringly high level of parental support for this
approach [22]. is approach does require careful pre-
liminary work, and the interventions represent options
that fall within reasonable norms of practice. However,
deferred or delayed consent has been determined to
be illegal in some jurisdictions (e.g. NSW Clinical and
Administrative Tribunal, under the Guardianship Act,
Australia). e process of how best to approach families
whose child dies after randomisation but before there
has been time for a consent discussion is an area of active
research.
Important clinical studies in2016
e developments described above have assisted recent
investigations into core elements of paediatric critical
care. An example is e National Emergency Airway
Registry for Children (NEAR4KIDS) registry, which
has provided invaluable data on safety issues related
to intubation. A study of 5232 children showed that
the staff seniority had no impact on the risk of com-
plications of intubation during a cardiac arrest [23].
Family presence during 4969 tracheal intubations was
safe and did not disturb the manoeuvre [24]. However,
another study of 3382 critically ill children with acute
respiratory failure showed that the number of tracheal
intubation attempts mattered: it was associated with
desaturations and increased occurrence of tracheal
Fig. 1 Selected areas of uncertainty facing a pediatric intensivist at a typical bedside. Clinical research evidence is required most, if not all, of the
basic processes of critical care for children. NIV non-invasive ventilation, NAVA neurally adjusted ventilatory assist, HFOV high frequency oscillatory
ventilation, APRV airway pressure release ventilation, SpO2 peripheral oxygen saturations)

Table 2 Selected recent examples ofpublications utilising the value oflarge, multiple centre prospective registry datasets describing more than1500 critically
ill children
Research network/collaborative group/registry/data‑
base Study title Participants Findings
American Heart Association’s get with the guidelines—
Resuscitation Investigators [26]Association between tracheal intubation during paediatric
in-hospital cardiac arrest and survival 2294 The study findings do not support the current emphasis on
early tracheal intubation for paediatric in-hospital cardiac
arrest
ANZICS Paediatric Study Group [77] Mortality related to invasive infections, sepsis, and septic
shock in critically ill children in Australia and New Zea-
land, 2002–13: a multicentre retrospective cohort study
97,127 Severe infections remain a major cause of mortality in paedi-
atric ICUs, representing a major public health problem
ANZICS paediatric study group [78] Variation in duration of respiratory support among Austral-
ian and New Zealand paediatric intensive care units 31,358 There is unit-level variation in length of stay and duration of
respiratory support, not accounted for by case-mix
ANZICS PSG and PICANET [79] Paediatric index of mortality 3: an updated model for pre-
dicting mortality in pediatric intensive care 53,112 Paediatric Index of Mortality 3 provides an international
standard based on a large contemporary dataset for the
comparison of risk-adjusted mortality among children
admitted to intensive care
CPCCRN [80] The Pediatric Risk of Mortality Score: Update 2015 10,078 The new Pediatric Risk of Mortality (PRISM) IV algorithm for
survival and death has excellent prediction performance
GFRUP [81] PELOD-2: an update of the Paediatric Logistic Organ Dys-
function score 3671 PELOD-2 score allows assessment of the severity of cases of
MODS in PICU with a continuous scale. The PELOD-2 score
now includes mean arterial pressure and lactataemia in the
cardiovascular dysfunction, and does not include hepatic
dysfunction
ICCON investigators [82] Impact of operative and postoperative factors on neurode-
velopmental outcomes after cardiac operations 1770 Operative factors may be less important than innate patient
and preoperative factors and postoperative events in pre-
dicting early neurodevelopmental outcomes after cardiac
operations in infants
PALISI network (SPROUT) [83] Global Epidemiology of Pediatric Severe Sepsis: the Sepsis
Prevalence, Outcomes, and Therapies Study 6925 Paediatric severe sepsis remains a burdensome public health
problem, with prevalence, morbidity, and mortality rates
similar to those reported in critically ill adult populations.
International clinical trials targeting children with severe
sepsis are warranted
PALISI network (NEAR4KIDS) [24] Family presence during paediatric tracheal intubations 4969 Family presence during tracheal intubation can safely be
implemented as part of family-centred care model in the
PICU
PALISI network (NEAR4KIDS) [23] Cardiac arrests associated with tracheal intubations in
PICUs: a multicentre cohort study 5232 Tracheal-intubation cardiac arrests occurred during 1.7% of
PICU tracheal intubations. Acute haemodynamic instability
and oxygen failure are risk factors
PICANet [84] Effect of specialist retrieval teams on outcomes in children
admitted to paediatric intensive care units in England and
Wales: a retrospective cohort study
57,997 These findings support the policy of combining centralisa-
tion of intensive care services for children with transfer by
specialist retrieval teams
PICANet [85] Characteristics and outcome of children admitted to adult
intensive care units in England, Wales and Northern
Ireland (1996–2011)
13,430 The number of children admitted to adult intensive care
units in England, Wales and Northern Ireland has been
steadily declining since 1996

intubation-associated events [25]. A retrospective
study of 2294 children with in-hospital cardiac arrest
showed that survival was lower in patients intubated
than not intubated [26]; the conclusion was that their
data do not support “early tracheal intubation”. Extuba-
tion is also a concern. A study of 409 children showed
that we should not use pressure support during extuba-
tion readiness tests [27], and that oesophageal manom-
etry can help detect upper airway obstruction almost
immediately after extubation [28].
Similarly, we are learning important new facts about
the complex intervention of mechanical ventilation. A
propensity-matched retrospective clinical study that
included 20,106 children receiving ventilation for acute
lung injury reported worse outcome and increased
hospital costs in the 859 (4.3%) who received inhaled
nitric oxide (NO, 20ppm during at least 24 h) [29]; an
RCT must be done to study the efficacy of NO in PICU
patients with acute lung injury. On the other hand, low
cardiac output syndrome (15 vs. 31%, p= 0.007) and
ECMO (1 vs. 8%, p=0.014) were less frequent in 97 chil-
dren who were exposed to NO (20ppm) during cardio-
pulmonary bypass versus 101 who were not [30].
Fivez et al. [15] randomised 1440 critically ill chil-
dren to receive early parenteral nutrition (within 24h
of PICU admission), or late parenteral nutrition (not
before the 8th day in PICU). Fluid input was balanced
in the two groups. All patients in Leuwen and Rotter-
dam received insulin infusions, as did most of them in
Edmonton. In the late group, the risk of contracting an
infection was 10.7% while it was 18.5% in the early group
(adjusted odds ratio 0.48; 95% CI 0.35–0.66; p<0.001).
PICU stay was shorter in the late than in the early
group (6.5±0.4 vs. 9.2±0.8 days, p=0.002), as well
as the length of mechanical ventilation (p=0.001). e
authors concluded that withholding parenteral nutrition
is “clinically superior” to early parenteral nutrition. is
is probably applicable to all PICU patients who received
insulin infusion. However, fewer patients experienced
episodes of severe hypoglycaemia (glucose <40 mg/
dL or 2.22mmol/L) in the early than in the late strat-
egy (35 vs. 65, p=0.001). In the discussion, Fivez and
colleagues wrote, “brief episodes of hypoglycaemia…
were not shown to have a negative effect on long-term
neurocognitive outcomes”. is statement is challenged
by Sadhwani etal. [31] who reported “a possible asso-
ciation between moderate to severe hypoglycaemia and
poorer neurodevelopmental outcomes at 1year of age”.
e safety of late parenteral nutrition in PICU patients
remains to be shown, at least when tight glycaemic con-
trol is used.
e efficacy of tight glycaemic control was questioned
by the PICS-SG CHiP Investigators [14]. It is again
ANZICS Australian and New Zealand Intensive Care Society, CPCCRN Collaborative Pediatric Critical Care Research Network, GFRUP Groupe Francophone de Réanimation et Urgences pédiatriques, ICCON International
Cardiac Collaborative on Neurodevelopment, PALISI pediatric acute lung injury and sepsis investigators, PICANet Pediatric Intensive Care Audit Network, PICS-SG Pediatric Intensive Care Society Study Group, TIPNet
Pediatric Intensive Therapy Network
Table 2 continued
Research network/collaborative group/registry/data‑
base Study title Participants Findings
Society of thoracic surgeons congenital heart surgery
database [86]Congenital heart surgery case-mix across North American
centres and impact on performance assessment 112,140 There is wide variation in congenital heart surgery case-mix
across centres
TIPNet study group, italian permanent registry [87] The importance of mortality risk assessment: validation of
the Paediatric Index of Mortality 3 score 11,109 Mortality indices require validation in each country where
it is used. The new Paediatric Index of Mortality 3 score
performed well in an Italian population
Virtual pediatric systems database [29] Effect of inhaled nitric oxide on outcomes in children with
acute lung injury: propensity-matched analysis from a
linked database
20,106 Inhaled nitric oxide administration is not associated with
improved mortality in mechanically ventilated children
with acute lung injury

challenged by the Heart And Lung Failure—Pediatric
Insulin Titration (Half-PINT) trial [32]. Cardiac sur-
gery patients were excluded in this 35-centre RCT that
enrolled 360 critically ill children allocated to a lower-
target group (glycaemia between 80 and 110 mg/dL or
4.4–6.1mmol/L) and 353 to a higher-target group (150–
180mg/dL or 8.3–10.0mmol/L). e median number of
PICU-free days was similar in the higher versus lower
target groups: 19.4 days (IQR 0–24.2) versus 19.4 days
(IQR 6.7–23.9), respectively (p=0.58). ere were more
infections in the lower group (3.4 vs. 1.1%) and more epi-
sodes of blood glucose level <40mg/dL (2.2mmol/L) (5.2
vs. 2.0%, p=0.03). e conclusion was that critically ill
children with hyperglycaemia do not benefit from tight
glycaemic. e remaining question is: what is the cost/
benefit of any blood glucose control in PICU patients?
In the CATCH trial, 1485 PICU patients were ran-
domised to receive standard central venous catheter
(CVC), antibiotic-impregnated CVC or heparin-impreg-
nated CVC; antibiotic-impregnated CVC significantly
decreased the risk of bloodstream infections [21]. e
efficacy of this measure is clear; what remains to be char-
acterised is its effectiveness.
e Infection Systemic Inflammation Sepsis section of
the European Society of Paediatric and Neonatal Inten-
sive Care (ESPNIC) created and validated a new defini-
tion of refractory septic shock (RSS) in a cohort of 424
children (11.6% mortality) from six PICU. Two RSS
scores were created: one was calculated at the bedside,
the other one by computer. e areas under the receiver
operating characteristics curves were 0.920 (95% CI
0.89–0.94) and 0.956 (95% CI 0.93–0.97), respectively.
A bedside RSS score ≥2 or a computed RSS score ≥3.5
was associated with a significant increase risk of mortal-
ity. e RSS can be used to enrol in clinical trials chil-
dren with severe shock and can be used as an outcome
measure in clinical trials run in PICU [33]. More gener-
ally, there is an urgent need to validate new definitions
of paediatric sepsis and septic shock, especially in coun-
tries where the profile of infection is very different from
wealthy countries.
What are the remaining areas ofuncertainties?
Table3 lists large funded studies currently underway but
unpublished in various research collaboratives; this list is
not exhaustive, but it gives a flavour of currently funded
research priorities [34]. e subjects being studied reflect
areas of significant uncertainty but also those that have
been considered tractable by both researchers and grant
panels. is naturally introduces a bias into the subject
matter but does reflect those that have met all these
demanding standards and are actually in progress. Some
themes can be identified in this cluster of studies.
Ventilatory assistance
Mechanical ventilation is becoming better adapted to
patients’ needs. For example, modes that assist rather
than control patients’ own ventilation decrease the res-
piratory workload and increase patients’ comfort. Modes
of ventilation like neurally-adjusted ventilatory assist
improve patient/ventilator synchrony, and may result in
better outcomes [35]. e question of how and when to
best use non-invasive ventilation in children is another
one for which we need answers; studies on this question
are underway (e.g. the FIRST-line support for Assistance
in Breathing in Children Feasibility Study).
Resuscitation withuids
It is frequently stated that “fluid resuscitation is the
gold standard for the initial treatment of early shock”
[36]. However, data of the Fluid Expansion As Support-
ive erapy (FEAST) study that enrolled 3141 African
children with severe febrile illness and impaired perfu-
sion provided powerful evidence against fluid boluses
in a low-resource environment [37]. What should be
the role of fluid bolus in PICU patients? e Canadian
‘SQUEEZE’ study (septic shock reversal is quicker in
paediatric patients randomised to an early goal-directed
fluid-sparing strategy vs. usual care) (NCT01973907) and
the UK’s ‘FiSh’ study (Fluids in Shock: ISRCTN15244462)
(UK Health Technology Assessment Programme
13/04/105) may start to fill this evidence gap [38].
Transfusion
Blood transfusion is the most common procedure per-
formed during hospitalisations in United States (http://
www.ahrq.gov). Severe anaemia significantly increases
the risk of death in critically ill patients. Red blood cell
transfusion is the only way to treat rapidly such anaemia.
However, blood products are overused and misused. We
learned in the last decade that it is safe to use a restrictive
red blood cell transfusion strategy (threshold haemoglo-
bin for transfusion 70g/L) in haemodynamically stable
PICU patients without a cyanotic cardiopathy or a con-
genital anaemia [11]. ere are also data suggesting that a
threshold of 90g/L is safe in children with stable cyanotic
cardiopathy [12]. On the other hand, the risk of mortal-
ity was higher in African hospitalised children with res-
piratory symptoms and with a haemoglobin level below
50g/L who were not transfused; this suggests that PICU
patients with a haemoglobin level below 50g/L should be
transfused [39]. What remains to be determined is what
to do in stable children with a haemoglobin level between
50 and 70g/L, in unstable patients and in patients with
some specific diseases like congenital anaemia. e
length of storage of red blood cell units (up to 42days)
is another concern. Many paediatric intensivists believe

Table 3 Randomised controlled trials currently funded andin progress bypaediatric critical care research networks
Research network/col‑
laborative group Study title Trials registration Number ofcentres Recruitment Intervention Primary outcome
measure Status
ANZICS PSG Sedation practice in
paediatric intensive
care in Australia and
New Zealand:
Baby-SPICE pilot study
ACTRN12614000225617 8 60 Comparison of current
sedation practice with
a dexmedetomidine
based sedation regi-
men that minimises
benzodiazepines
Feasibility (separation
between groups for
light sedation in first
48 h)
Analysis
CCCTG EPOCH/evaluating pro-
cesses of care and the
outcomes of children
in hospital
NCT01260831 22 100,000 Implementation of
bedside paediatric
early warning system
(PEWS) vs. standard
care
All cause hospital
mortality Analysis
CCCTG SQUEEZE Trial Pending 8 0 Fluid Sparing Resuscita-
tion Strategy Difference in time to
shock reversal Ready to start
CCCTG STRIPES/steroid use in
paediatric fluid and
vasoactive infusion
dependent shock -
pilot study
NCT02044159 7 57 Hydrocortisone vs.
placebo Feasibility (patient
accrual rate over one
year)
Analysis
GFRUP Efficacy of IntraVenous
ImmunoGlobulins in
Toxic Shock Syn-
dromes: a Paediatric
Pilot Study (IVIG)
NCT02219165 9 15 Randomised trial:
intravenous human
immunoglobulin vs.
albumin
Feasibility (patient
accrual rate over two
year)
Recruitment
PICS-SG “SCARF”/randomised
study of early CPAP in
acute respiratory Fail-
ure in children with
impaired immunity
ISRCTN82853500 3 42 Early ICU admission for
CPAP vs. standard care Need for intubation Analysis
PICS-SG FIRST-ABC/first-line sup-
port for assistance in
breathing in children
feasibility study
NCT02612415 3 121 High flow humidified
oxygen vs. CPAP Recruitment
(feasibility of a definitive
study)
Recruitment complete
Data validation
PICS-SG FiSh/fluid in shock study ISRCTN15244462 4 108 Pilot randomised
controlled study of
conservative vs. liberal
fluid resuscitation in
shock study
Recruitment
(feasibility of a definitive
study)
Open to recruitment
PICS-SG Oxy-PICU/A randomised
pilot multiple centre
trial of conservative
vs. liberal oxygenation
targets in critically Ill
children
ISRCTN in progress 3 120 Oxygen saturation
targets 88–92% vs.
95–100%
Recruitment
(feasibility of a definitive
study)
Recruiting from January to
August 2017

that fresh blood, stored less than a week, is better, even
though no hard data support this point of view [40].
ree large RCTs in adults [41–43] and one in very low
birth weight premature [44] showed that fresh blood
offers no advantage, at least up to 28days of storage. A
large international RCT, the Age of Blood in Children in
PICU study (ABC-PICU: NCT01977547), should answer
the question. e National Heart, Lung and Blood Insti-
tute (NHLBI) wrote, “studies on transfusion therapy for
paediatric patients… are urgently required” [45]. Accord-
ingly, the NHLBI suggested trial opportunities and pri-
orities in paediatric transfusion medicine: transfusion
trigger (red blood cell, plasma and platelets), anaemia
tolerance, transfusion in specific population (cardiac sur-
gery, unstable PICU patients), length of storage of blood
products, safety, etc. [45, 46].
Understanding vital signs/goal‑directed therapy
Perhaps the most striking deficit in paediatric critical
care knowledge is that we do not know the optimal values
for vital signs, including oxygen saturation, temperature,
blood pressure and others even in common scenarios.
New high-resolution physiological data capture sys-
tems offer the potential to understand both physiology
and practice in a way that has not been possible previ-
ously [47]. More conservative target for vital signs, in
line with a general move to more conservative manage-
ment described above, is a subject of active investigations
(Table3).
Physiological targets can be integrated into treatment
protocols, and ‘goal-directed therapy’ is appealing as a
way of titrating care to individuals needs. ere are more
and more data showing that using protocolised preven-
tion or treatment strategy improved patients’ outcomes.
e main problem with protocols is in defining the best
goal to direct therapy. For example, early goal-directed
therapy aiming to maintain ScvO2 over 70% was sug-
gested as a clinically useful target in children with severe
sepsis [48], but recent large RCTs did not support this
statement in adults [49, 50], perhaps reflecting improve-
ments in standard care. More studies are needed to find
the best vital goals in many conditions observed in PICU.
Multiple organ dysfunction syndrome
e US National Institute of Child Health and Human
Development (NICHD) identified two priorities in pae-
diatric critical illness research in 2016 [51]. e first was
to improve our knowledge on paediatric MODS. e fol-
lowing questions were raised.
•Can we improve the diagnostic criteria of paediatric
MODS?
•What is the epidemiology of paediatric MODS [52]?
ANZICS PSG Australia and New Zealand Intensive Care Society Paediatric Study Group, CCCTG Canadian Critical Care Trials Group, GFRUP Groupe Francophone de Réanimation et Urgences pédiatriques, ICU intensive care
unit, MODS multiple organ dysfunction syndrome, PALISI paediatric acute lung injury and sepsis investigators, PICS-SG Pediatric Intensive Care Society Study Group, PICU pediatric ICU
Table 3 continued
Research network/col‑
laborative group Study title Trials registration Number ofcentres Recruitment Intervention Primary outcome
measure Status
PICS-SG Fever/A randomised
pilot multiple centre
trial of conservative
vs. liberal approach to
fever in critically Ill chil-
dren with suspected
infection
ISRCTN in progress 4 125 Treat fever at 37.5 °C vs.
39.5 °C Recruitment
(feasibility of a definitive
study)
PICS-SG SANDWICH/cluster
randomised trial seda-
tion and weaning in
children
In progress 15 12,000–14,000 Protocol-based nurse-
led sedation, weaning
and extubation readi-
ness testing vs. current
care
Duration of mechanical
ventilation Recruiting from February
2017 to Augsut 2020
PALISI/CCCTG (Blood Net
subgroup) ABC-PICU/Age of blood
in children in PICU NCT01977547 >40 1538 Red blood cell units
stored 7 days or less vs.
standard delivery red
blood cell units
New or progressive
MODS On-going

•Can we improve our understanding of the patho-
physiology of MODS?
•What is the best way to estimate and to monitor the
severity of cases of paediatric MODS: scores, bio-
markers, technical devices measuring markers like
heart rate variability in a continuous fashion [53, 54]?
•Can we improve the prevention and treatment of
paediatric MODS?
•What long-term outcomes are associated and/or
attributable to MODS [52]?
e NICHD launched a request for application in
2016 to support a large research program on paediatric
MODS.
Trauma
Another priority of the NICHD is “understanding the
pathophysiology of paediatric trauma to optimise treat-
ment outcomes and prevent future difficulties in chil-
dren”; the NICHD added, “research identifying the social
and behavioral causes and consequences of paediatric
trauma, and the strategies to prevent and mitigate risk for
trauma will be high priorities” [51]. All types of trauma
will be considered, including physical and psychologi-
cal child maltreatment [55]. Many initiatives on brain
trauma are already on-going. For example, finding bio-
markers that would help bedside practitioners to estimate
the severity of the brain dysfunction and the prognosis of
children with traumatic brain injury is a priority [56].
Safety
Safety is another important concern. Antibiotic over-
use contributes to the development of resistance. e
National Summit on Overuse held in July 2013 identified
five overused treatments that can harm patient safety and
quality: antibiotic use for common cold was ranked first
(http://www.jointcommission.org/overuse_summit/).
Starting antibiotics in PICU patients as soon as an infec-
tion is suspected is the right thing to do: in critically ill
patients, the risk of mortality is increased if antibiotic
treatment is delayed [57]. It is because we are slow to stop
antibiotics that there is an increased antibiotics pressure
and more resistance to antimicrobials. Improving antibi-
otic use should improve the outcomes of PICU patients
and decrease health system expenses.
We expect that many other safety issues will be raised
in the forthcoming years.
Comfort
In the 1980s, we learnt that pain and anxiety could kill
children. Later on, we learnt that giving some analgesia
and sedation saves life. us, giving pain-killing and sed-
ative drugs became standard; huge doses are sometimes
used. In the last decade, some data suggested that too
much analgesia or sedation might be a cause of neuro-
logical sequelae, like disturbed cognitive development
[58]. Papers can be found in the medical literature on
scores or devices estimating the level of sedation and of
comfort, and diagnostic criteria of delirium [59, 60]. We
must determine the safety of analgesia and sedation in
critically ill children, and learn how to optimise their use
in PICU. Better end-of-life and palliative care and more
attention to parents’ actual experiences are other impor-
tant concerns.
Children withmedical complexity
Children with medical complexity now comprise more
than one-half of PICU admissions in the United States
and account for the vast majority of all ICU therapies,
including 86% of mechanical ventilation days, 78% of
arterial catheters, 77% of central venous catheters, and
89% of ECMO runs [61]. is population of children
gives every indication of growing, as intensivists are
increasingly adept at preventing death but often leave
survivors with complex medical conditions requiring
long-term medical care—e.g. children with hypoplastic
left heart syndrome [62], bone marrow and solid organ
transplant survivors [63–65]. Research on the underlying
conditions remains the purview of other subspecialists
but the recurrent hospital care for these children fre-
quently falls by default to the paediatric intensivist.
Unfortunately, paediatric intensivists are poorly
equipped both by training and temperament to accept
the role of primary caregivers for the children often
referred to as “frequent flyers”. Children with sickle cell,
diabetes, asthma, epilepsy, cerebral palsy, cystic fibrosis,
and many other chronic diseases are repeatedly hospital-
ised in our PICUs at an estimated annual cost of US$7.6
billion in the United States [61]. Improving the care of
these children should be high on our research agenda.
Post‑PICU morbidity
Decreases in short-term mortality of critically ill chil-
dren results in a shift of the outcomes relevant to PICU
patients from mortality to post-PICU outcomes. ere
is growing recognition of the importance of describ-
ing long-term outcomes and cost-effectiveness analyses.
Post-intensive care syndrome—a name suggested by the
Society of Critical Care Medicine (SCCM)—includes
many complications like vocal cord dysfunction, dysp-
nea, hypermetabolic syndrome, cardiac arrhythmias,
post-thrombotic syndrome, bone and muscle pain, neu-
rodevelopmental delay, ICU-acquired weakness myopa-
thy, sleep disorder, swallowing and/or feeding problems,
weight loss, chronic kidney dysfunction, behaviour prob-
lems, post-traumatic stress disorders, depression, anxiety,

anaemia, decreased health-related quality of life, etc. e
SCCM also defined a post-intensive care syndrome fam-
ily, which includes burnout, post-traumatic stress disor-
der, anxiety, and depression [66, 67]. ese problems are
frequent and under-recognised, and most of the time
they are not addressed [68].
Preliminary work in palliative care and advanced care
planning show promise in clarifying care goals and pro-
viding psychological as well as medical support beyond
the PICU [69]. e potential value of PICU “follow-up”
clinics where consultation with other subspecialists and
primary care providers can be coordinated in both time
and place is beginning to be considered [70]. Similarly,
telemedicine and the internet offer promise to extend
PICU expertise into the homes of chronically ventilated
kids and possibly decrease their many emergency depart-
ment visits and brief hospital admissions [71]. ere are
data suggesting that peri-PICU and post-PICU rehabili-
tation program can improve the outcome of PICU sur-
vivors [9]. e SCCM and the National Institutes for
Health (NIH) and Clinical Excellence (NIHCR) recom-
mend organising post-ICU outpatient clinics in order to
diagnose complications and sequelae and to treat them
appropriately.
Research is needed on how to better care for these chil-
dren—how to improve continuity of care, where best to
establish a medical home, and how to coordinate care
with other subspecialists and (ideally) primary care pro-
viders [72]. e following questions must be addressed:
•What are the mid-term and long-term outcomes of
children who survive to a PICU stay?
•Can we prevent and/or treat these complications
more appropriately?
•Can we characterise surrogate outcomes that can be
monitored in the PICU and that are closely associ-
ated not only to PICU mortality but also to mid-term
and long-term post-PICU adverse outcomes?
Innovative RCTs/knowledge transfer
Most RCTs conducted with critically ill children or adults
give negative results, i.e. they were unable to determine
if a given treatment makes a statistically significant dif-
ference. RCTs can be negative because there is a lack
of power (too small sample size), by chance alone and/
or because there is no efficacy at least within the stud-
ied population. For example, many RCTs have reported
no benefit of hypothermia in severe traumatic brain
injury [13, 73]. It is valuable to learn that a treatment
shows no efficacy and/or causes more harm than benefit,
because this answers the question: should this treatment
be used? However, this answer is limited to the setting,
case-mix, resources and other practices at the time in
the participating centres. We believe that more atten-
tion must be paid to innovative designs of RCT in order
that more superiority and/or non-inferiority RCTs report
statistically significant results. Examples of innovative
design include large pragmatic RCT, n-of-1 RCT, stepped
wedge RCT, cluster RCT, RCT on big data, Bayesian RCT
and adaptive RCT (a series of papers on innovative RCTs
were published in 2016 [74]).
Applying findings of RCTs is also a big challenge. Lack
or lag of knowledge application is considered an impor-
tant problem by the American National Institutes of
Health (NIH) and the Canadian Institutes of Health
Research (CIHR). Barriers to knowledge transfer can be
scientific or administrative, such as lack of leadership,
while barriers can also be due to social, cultural or reli-
gious issues. ese barriers can be overcome by multi-
faceted interventions that promote physician behavioural
change, i.e. a combination of at least two of the follow-
ing actions: lectures, audit, feedback, consensus pro-
cess, educational outreach visits, local opinion leaders,
patient-mediated interventions, reminders—manual or
computerised—and marketing [75]. How to overcome
these barriers to knowledge application must be studied
in PICU, not only with RCTs but also with qualitative
research, surveys, descriptive studies, evaluative research
and cost/benefit analyses.
What the international group ofexperts
recommend asthe top ten research topics tobe
studied inthe next10years andwhat are the
expected outcomes/results ofthese studies?
e authors of this paper believe that much atten-
tion must be paid to at least the following ten research
themes. ese are likely to change, both in response to
developments outside of our speciality, such as new
research, including immunisations and gene therapies,
and factors outside of medicine, including changing soci-
etal views of what represents value in healthcare, climate
change, etc.
We again highlight the importance of such studies
being performed in low- and middle-income countries as
well as highly resourced PICUs. Risk and benefit profiles
may differ significantly between these settings.
1. Ventilation: ventilator-induced lung injury; weaning;
better interaction between ventilator and patient;
non-invasive mechanical ventilation.
2. Fluid therapy, transfusion and feeding strategies:
choice of product, thresholds for transfusion, rate,
targets and endpoints.
3. Treatment guidance: vital signs targets, physiologi-
cal or laboratory values in specific patient groups at a
point in their disease process.

4. Multiple organ dysfunction syndrome (MODS) and
sepsis: definition and diagnostic criteria based on
validated physiologic and/or laboratory markers,
pathophysiology, pathogens that caused very severe
disease (example: Ebola virus), treatment, prevention
of primary and secondary complications, relation-
ship between MODS and post-ICU outcomes.
5. Trauma: prevention and treatment, including neuro-
protection.
6. Safety: better antibiotic use, better monitoring, safer
communication strategies, etc.
7. Comfort of patients and their family: sedation, anal-
gesia, occupational therapy, palliative care, preven-
tion of anxiety, depression, family experience in
intensive care, etc.
8. Children with medical complexity: underlying condi-
tions, epidemiology, treatment strategy, and ethical
considerations.
9. Post-PICU outcomes: new morbidity post-PICU,
quality of life, early rehabilitation, etc.
10. Knowledge generation and application: when should
we use innovative clinical trials and can we improve
knowledge transfer by a better comprehension of
how physicians make their decisions and by provid-
ing better decision support tools?
is list is neither exhaustive nor exclusive, but it is
supported by recent clinical trials (Tables1, 2) and on-
going RCTs (Table3). e ranking is not important: the
tenth bullet (knowledge application) is as important as
the first one (ventilation).
In developed countries, we do not expect an impor-
tant decrease in the mortality rate presently observed in
PICU, but it is hoped that post-PICU health status will be
better characterised, and that the prevention and treat-
ment of mid-term and long-term post-PICU complica-
tions will be improved. Moreover, given the exploding
costs of critical care, the focus on health care value must
be increased. In countries that are less wealthy, mortality
is still high, and a research agenda specific to critically ill
children in these areas must be the highest priority.
Abbreviations
95% CI: 95% confidence interval; CVC: Central venous catheter; ICU: Intensive
care unit; MODS: Multiple organ dysfunction syndrome; NO: Nitric oxide; PICU:
Paediatric ICU; RCT: Randomised controlled trial; RSS: Refractory septic shock;
SCCM: Society of Critical Care Medicine.
Author details
1 Paediatric Intensive Care Society Study Group (PICS-SG), UCL Great Ormond
Street Institute of Child Health, London, UK. 2 PICU, Red Cross War Memorial
Children’s Hospital, School of Child and Adolescent Health, University of Cape
Town, Cape Town, Republic of South Africa. 3 Paediatric Intensive Care Unit,
the Children’s Hospital at Westmead, the Sydney Children’s Hospital Network,
Westmead, NSW, Australia. 4 Pediatric Intensive Care Unit, University Lille, CHU
Lille, EA 2694, Santé publique: épidémiologie et qualité des soins, 59000 Lille,
France. 5 Pediatric Emergency and Critical Care Department, H Clinicas, UFRGS
University, Porto Alegre, Brazil. 6 Pediatric Acute Lung Injury and Sepsis Investi-
gators (PALISI Network), Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA.
7 Executive Committee, PALISI, John Mickell Professor of Pediatric Critical Care,
Children’s Hospital of Richmond at VCU, Richmond, VA, USA. 8 Réanimation
Pédiatrique et Médecine Néonatale, Hôpitaux Universitaires Paris-Sud AP-HP,
Le Kremlin-Bicêtre, France. 9 Pediatric Interest Group, Canadian Critical Care
Trials Group, Montreal, Canada. 10 Division of Pediatric Intensive Care Medicine,
Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Sainte-
Justine Hospital, Room 3431, 3175 Côte Sainte-Catherine, Montreal, QC H3T
1C5, Canada.
Author contributions
MP and JL drafted the manuscript. All authors read, improved and approved
the final version of the manuscript.
Compliance with ethical standards
Conflicts of interest
None.
Source of funding
None.
Support
None.
Received: 27 December 2016 Accepted: 16 February 2017
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