Prevention of Hospital-acquired Infection in VLBW Infants. The EuroNeoKiss trial.

128 Pages·2012·2.53 MB·English

3rd International Congress of UENPS 2012, Speakers, Acta Med Port 2012;25(S2):1-128 3rd International Congress of UENPS 2012, Speakers, Acta Med Port 2012;25(S2):1-128
Prevention of Hospital-acquired Infection in
VLBW Infants. The EuroNeoKiss trial. S
R
E
K
A
E
P
“Primum non nocere”. S
(Anonymous aphorism attributed to Hippokrates of Kos c. 460 BC – c. 370 BC).
Adolf VAllS-I-SOlER, Marisela MAdRId, Águeda AzPEItIA, Elena SANtEStEBAN, Casilda ARRÁNz
Acta Med Port 2012;25(S2):1-4
Great efforts have been put into the surveillance and is also available at national level, like that collected by the
prevention of hospital-acquired infection (HAI), an important “Spanish Grupo Casrtrillo”.6
problem affecting quality of care, since are responsible for HAI is potentially preventable, but achieving a septicae-
significant morbidity and mortality especially in patients ad- mia zero is an almost impossible goal. In adults, Haley et
mitted to intensive care units (UCINs). 1,2 al 7 showed that minimal effort could be reduced it by 6%,
In neonates, the most common expression of HAI is no- and the implementation of a specific control program could
socomial sepsis (NS), an entity not easy to detect early and achieve a 32% reduction. A review of 30 studies showed
to select effective treatment. Furthermore, the distinction a 20% decrease was possible.8 Additionally, its reduction
between perinatal or vertical and horizontally-transmitted has the potential to reduce mortality, morbidity and hospi-
or NS is not well defined. For practical reasons, vertically tal treatment cost associated with treating VlBW infants.
transmitted sepsis has been assimilated to early-onset sep- A study based on a large, multi-institutional population of
sis (EOS, diagnosed at <72 hours of life) and horizontally VlBW infants showed the increase in mean cost attributed
transmitted sepsis to late-onset sepsis (lOS, diagnosed > to NS varied from US$ 6276 for those with birth weight 1251
72 hours of life). to 1500 g to US $ 12,480 at birth weights of 751 to 1000 g.9
NS incidence has been rising, especially among the In newborn infants, much like in older children and adults,
very-low-birth-weight (VlBW; birth weight <1500 g) infants, NS is associated with three main risk factors: improper
with increase susceptible to infections due to the immatu- hand-washing, use of intravascular catheters and me-
rity of the immune system, poor skin protection, need for chanical ventilation. data from the neonatal component
repeated invasive procedures and exposure to numerous of “Krankenhaus-Infektions-Surveillance-System” (NEO-
caregivers. In fact, NS is a frequent and serious complica- KISS) in Germany, reported a 73% of NS and 81% of pneu-
tion and the most important risk factor not present at admis- monia associated with these devices.10
sion for adverse outcome. NS is associated with increased Several neonatal networks in Canada, USA, Australia,
mortality and short-term morbidities, longer hospital stay, New zealand, England and Japan, among others. these
3 and the risk for long-term disabilities Among important networks used data on infection surveillance to learn about
co-morbidities are severe intraventricular haemorrhage, variations in the health care provided to newborns. It has
periventricular leukomalacia, chronic lung disease (Cld), not only provided valuable information to NICUs but have
necrotizing enterocholitis and retinopathy of prematurity. strengthened the comparison and benchmarking between
these conditions in turn increase the need for invasive life- units within regions or countries, allowing different groups to
support interventions (intravascular catheters, intubation design intervention strategies and public health policies to
and mechanical ventilation) which raises again the risk of improve quality of care of these patients. those networks,
NS. by the use of common protocols have developed observa-
About 20% of all VlBW infants experience at least an tional studies, clinical trials and quality improvement initia-
episode of severe systemic infection during hospital stay, tives, as well as served as platforms to exchange scientific
and despite advances in intensive care and in antimicro- knowledge, experience and disseminate evidence at na-
bials, their mortality is three times higher in those without tional and international level on infection prevention.11,12
sepsis. In VlBW infants, sepsis accounts for approximately In Europe, the implementation of surveillance systems
half of all deaths beyond the second week of life. 4 for HAI has been rather scarce,13 been NeoKiss, specific
In Europe, according to data collected by European designed for VlBW infants by a panel of German neona-
Neonatal Network (ENN) from a cohort of 4,058 VlBW in- tologists and tested a pilot project, latter implemented in
fants treated in 71 centres over the years 2006-2007, over- 198 units. Now by law, all NICUs caring for VlBW infants
all NS incidence was 25%, with a wide inter-centre vari- have to use it to be reimbursed by the German Federal
ability (range 0-53.7%). NS was related to gestational age, Government. the Neo-Kiss system mainly focussed on
birth weight, gender, low 5-min Apgar score and need for surveillance of NS, pneumonia and NEC, and studied their
intubation at birth. Infants with NS had a highest risk for relation with catheters, ventilator devices and the use of an-
Cld, (OR 1.7 (95 % CI 1.4-2.17). their hospital stay was tibiotics.14,15
on average, 20 days longer and had an increased mortality German data suggest that participation in NeoKiss, and
rate (13.3%) that infants who did not developed NS. 5 dat providing individual units with feedback data, decreased
A.V-I-S., M.M., Á.A., E.S., C.A.: Neonatal Intensive Care and Neonatal Epidemiology Unit, Cruces University Hospital, University of the Basque country, Barakaldo-Bilbao, Spain.
Copyright © Ordem dos Médicos 2012
Revista Científica da Ordem dos Médicos 1 www.actamedicaportuguesa.com
3rd International Congress of UENPS 2012, Speakers, Acta Med Port 2012;25(S2):1-128 3rd International Congress of UENPS 2012, Speakers, Acta Med Port 2012;25(S2):1-128
table 1 - Estimates of the real impact of NS in VlBW infants born in Europe.
500 million Population of the EC 1
S s
PE ant
AKER W inf 5 million Newborns/year (Birth rate: 10 per thousand inhabitants (estimates))
S B
l
V
n
o
a 75 000 VlBW Infants in EC per year (1.5% of total births)
at
d
C
E
10 050 deaths of VlBW Infants in EC per Year (ENN mortality rate: 13.4%) 2
18 750 VlBW Infants have a NS in Europe NICU’s per year (ENN NS rate: 25%) 2
s
nt
a
nf Possible reduction of sepsis-related mortality in VlBW Infants in EC per year (61.3%
W I 3 218 sepsis related mortality over 5,250 excess of deaths compared with japanese mortality
B rates: 6.4%) 3
l
V
n
a i 112.5 million Cost saving if 30% of sepsis reduction per year and European NICU 4
at
d
S
N
Reduction of VlBW Infants with severe disabilities at 2 year of postnatal corrected age in
410
EC per year (severe disability rates for non-infected of 10.1% and 2.8%) 5
1 - EUROStAt
2 - ENN 2006-2007 5
3 - SEN1500 vs NRNJ Comparison 33
4- Estimation according to Hospital de Cruces annual costs
5 - Unpublished data
the incidence of NS by 24% from 8.3 to 6.4 NS/1,000 pa- tools for prevention of HAI and changes in culture habits of
tient-days in three years (OR 0.73, 95%CI 0.60–0.89).14 institutions involved in their studies.17,19,20
However, NEO-KISS efficacy was not evaluated by a ran-
domised study but rather by an observational sequential EuroNeoKiss clinical trial
analysis. Moreover, a multifaceted educational intervention It is necessary to develop a well constructed RCt based
program has been developed and is currently been evalu- on reliable scientific evidence that considers the multiple
ated by the same group, but again with a non-randomised factors involved in the transmission of NS. However, it is
before and after design. essential to implement interventions of proven clinical ef-
Nevertheless, information, by itself is not sufficient to ficacy that have been appropriately evaluated by well de-
produce improvements in care, if it is not translated into signed, large randomised clinical trials (RCt). Accordingly,
changes in clinical practice in order to improve outcomes. the EuroNeoNet initiative, funded via dGSANCO projects
Models currently used for prevention of infection are evi- EuroNeoStat I and II (2005/16 and 2008/1311), plans to
dence-based and combine interventions built-in continuous conduct such a large trial.
quality improvement initiatives. these models exemplify the We propose to conduct a step wedge, cluster-ran-
integration of results of clinical research into daily clinical domised RCt to accurately measure the real effect of the
practice, aiming to provide high quality care, focused on educational intervention on the rate of NS in VlBW infants,
systems that tend to be error-free in the implementation of and to monitor its effect using a standardised surveillance
effective change and to assess its impact.2 system. (Fig. 1) this study will also allow us to measure
Several groups have developed neonatal experimental separately the surveillance effect from the specific effect of
studies and RCt to evaluate strategies aimed to prevent NS. the intervention on the incidence of NS. We hypothesise
these combined intervention strategies basically consisted that its implementation will reduce by 30% the rate of NS in
on recollection and diffusion of scientific evidence and the VlBW infants assessed by the EuroNeoKiss.14
simultaneous application of a set of preventive measures the fast growth of technological and biomedical de-
with the establishment of an environment of intense mul- velopments has increased the survival of newborn infants,
tidisciplinary collaboration, in order to design and develop especially those of VlBW. Although they account only for
plans to improve the quality of care for patients. 8,13,16,-19 1-1.5% of newborns, it is estimated that 25% of them de-
Based on this philosophy, the Vermont-Oxford and velop NS which greatly increases their hospital stay, triples
Canadian Neonatal Networks developed a quality improve- mortality 3 and greatly compromise their future neurodevel-
ment system, that have shown that it is possible to reduce opment.
NS; and they have also generated valuable methodological Neonatologists see NS as the single most significant
Revista Científica da Ordem dos Médicos 2 www.actamedicaportuguesa.com
3rd International Congress of UENPS 2012, Speakers, Acta Med Port 2012;25(S2):1-128 3rd International Congress of UENPS 2012, Speakers, Acta Med Port 2012;25(S2):1-128
Study Design Diagram
S
R
E
K
A
E
P
Control Arm S
Surveillance
System
1 2 3
Survey SurveillanceSystem Survey SurveillaInncteerSvyesntteimon+A Irnmtervention Survey
Implementation
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42
Period1 Period 2 Period3 Period4
SurveillanceSystem Randomization
ResultsFeedback
Intervention Intervention Data
PreInterventionPhase
ImplementationPhase EvaluationPhase Analysis
Fig. 1 - Study design diagram
Survey 1,2,3: Survey of NS preventing knowledge
Period 1,2,3,4: Steps of the intervention implementation
hospital-acquired risk factor affecting clinical outcome. justified by several facts, related to the large impact of NI not
Furthermore, it is well known to be an at least partially pre- only by economic costs are outline on table 1. Moreover,
ventable factor, being estimated that overall a 20-30% in- the short- and long-term consequences of HAI in VlBW in-
cidence reduction is possible if appropriate measures are fants cause an even greater impact in terms of great stress
undertaken.8 Hence NS prevention in VlBW infants has especially to babies and his/her family, but also to health
become a major challenge for most NICUs. However, cur- workers and society.
rently, most European countries do not have a HAI surveil-
lance systems adapted for newborns and aimed to collect AcKNoWLEdgEMENT
information in a consistent, standard and systematic way this work was supported in part by the “Instituto de Salud
among different units and areas, to enable to compare risks Carlos III”, Ministry of Economics, grant supporting the
and facilitate the development of specific interventions tar- Research thematic Network of Maternal and Child Health
geted to achieve a substantial reduction in infection rates.13 and development Network (Red SAMId, Rd08/0072).
the importance of this infection-prevention RCt seems Web: euroneonet.org
REFERENcES
1. Hemming VG, Overall JC, Jr., Britt MR. Nosocomial infections in a Castrillo”. J Perinat Med. 2002;30:149-157.
newborn intensive-care unit. Results of forty-one months of surveil- 7. Haley RW, Culver dH, White JW, Morgan WM, Emori tG, Munn VP,
lance. N Engl J Med. 1976;294:1310-1316. et al. the efficacy of infection surveillance and control programs in
2. Bishop-Kurylo d. the clinical experience of continuous quality im- preventing nosocomial infections in US hospitals. Am J Epidemiol.
provement in the neonatal intensive care unit. J Perinat Neonatal Nurs. 1985;121:182-205.
1998;12:51-57. 8. Harbarth S, Sax H, Gastmeier P. the preventable proportion of noso-
3. Stoll BJ, Hansen N, Fanaroff AA, Wright ll, Carlo WA, Ehrenkranz comial infections: an overview of published reports. Journal of Hospital
RA, et al. late-onset sepsis in very low birth weight neonates: the Infection. 2003;54:258-266.
experience of the NICHd Neonatal Research Network. Pediatrics. 9. Payne NR, Carpenter JH, Badger GJ, Horbar Jd, Rogowski J. Marginal
2002;110:285-291. increase in cost and excess length of stay associated with nosocomial
4. Stoll BJ, Hansen N. Infections in VlBW infants: studies from the NICHd bloodstream infections in surviving very low birth weight infants 306.
Neonatal Research Network. Semin Perinatol. 2003;27:293-301. Pediatrics. 2004;114:348-355.
5. Valls-i-Soler A, Azpeitia A PJI, EuroNeoNet Group. Hospital – 10. Geffers C, Baerwolff S, Schwab F, Gastmeier P. Incidence of health-
Acquired infection in very –low-birth-weight infants: Risk Factors and care-associated infections in high-risk neonates: results from the
Consequences. 9-10-2009. 50th Annual Meeting of the European German surveillance system for very-low-birthweight infants. J Hosp
Society of Paediatric Research, Hamburg, Germany. Infect. 2008;68:214-221.
6. lopez Sastre JB, Coto Cd, Fernandez CB. Neonatal sepsis of noso- 11. Valls A, Halliday Hl, Hummler H. International Perspectives: Neonatal
comial origin: an epidemiological study from the “Grupo de Hospitales Networking: A European Perspective. NeoReviews. 2007;8:e275-e281.
Revista Científica da Ordem dos Médicos 3 www.actamedicaportuguesa.com
3rd International Congress of UENPS 2012, Speakers, Acta Med Port 2012;25(S2):1-128 3rd International Congress of UENPS 2012, Speakers, Acta Med Port 2012;25(S2):1-128
12. Vergnano S, Menson E, Kennea N, Embleton N, Russell AB, Watts bloodstream infection in neonatal intensive care. Clin Perinatol.
t, et al. Neonatal infections in England: the NeonIN surveillance net- 2010;37:247-272.
work. Archives of Disease in Childhood - Fetal and Neonatal Edition. 17. Kilbride HW, Powers R, Wirtschafter dd, Sheehan MB, Charsha
S 2011;96:F9-F14. dS, laCorte M, et al. Evaluation and development of potentially bet-
P
E 13. Coello R, Gastmeier P, de Boer AS. Surveillance of hospital-acquired ter practices to prevent neonatal nosocomial bacteremia. Pediatrics.
A
K infection in England, Germany, and the Netherlands: will internation- 2003;111:e504-e518.
ER al comparison of rates be possible? Infect Control Hosp Epidemiol. 18. lee SK, Aziz K, Singhal N, Cronin CM, James A, lee dS, et al.
S 2001;22:393-397. Improving the quality of care for infants: a cluster randomized con-
14. Schwab F, Geffers C, Barwolff S, Ruden H, Gastmeier P. Reducing trolled trial. CMAJ. 2009;181:469-476.
neonatal nosocomial bloodstream infections through participation in a 19. Stevens B, lee SK, law MP, Yamada J. A qualitative examination of
national surveillance system. J Hosp Infect. 2007;65:319-325. changing practice in Canadian neonatal intensive care units. J Eval
15. Soler A, Madrid M, Geffers C, Hummler Hd. International Perspectives: Clin Pract. 2007;13:287-294.
Preventing Sepsis in VlBW Infants: Experience from Neonatal 20. Horbar Jd, Rogowski J, Plsek PE, delmore P, Edwards WH, Hocker
Networks and Voluntary Surveillance Systems. NeoReviews. J, et al. Collaborative quality improvement for neonatal intensive care.
2010;11:e403-e408. NIC/Q Project Investigators of the Vermont Oxford Network. Pediatrics.
16. Powers RJ, Wirtschafter dW. decreasing central line associated 2001;107:14-22.
Revista Científica da Ordem dos Médicos 4 www.actamedicaportuguesa.com
3rd International Congress of UENPS 2012, Speakers, Acta Med Port 2012;25(S2):1-128 3rd International Congress of UENPS 2012, Speakers, Acta Med Port 2012;25(S2):1-128
EuroNeoNet.
A Platform for Neonatal clinical trials. S
R
E
K
A
E
P
S
“Children remain therapeutic orphans”
H Shirley, MD (J Pediatr 1968;72:119-120).
Adolf VAllS-I-SOlER, Elena SANtEStEBAN, Marisela MAdRId
Acta Med Port 2012;25(S2):5-7
BAcKgRoUNd
Although the 20% Europe’s population (500 million) and development.
40% in the world is under 18 years, 70% of registered medi- Finally, we note that the last frontier of pediatric phar-
cations do not include sufficient paediatric data,2 particularly macology is the pregnant woman10 and their fetuses.11. little
in relation to the dosage regime. Almost 50% of medicines is known of the PK/Pd of drugs used in pregnant women,
used in hospitalised children have no paediatric data in the which until recent years were not included in RCts.12 Re-
label. In addition, 50 to 75% of the drugs used, which have garding fetal pharmacology, very little progress has been
not been adequately tested in children, percentage that made, only been successfully addressed a small number of
reaches 90% in neonates.3,4 pathological processes, been the main success pharmaco-
In addition, the use of pharmaceutical preparations not logical induction of fetal lung maturity with antenatal corti-
designed for the pediatric population, involves an increase costeroid administration. However, fetal therapy raises ethi-
in medication errors, especially in neonates.5 A recently cal issues regarding the balance of benefits and potential
published study described a significant association be- harms, informed consent, and the duties of the physician
tween medication errors and the use of medications without toward pregnant women and the fetus.13,14
pediatric indication 6.
the dilemma faced by pediatricians is to choose be- Initiatives to change the therapeutic orphan status of
tween avoiding the risks of using unproven medications in neonates.
children or deny treatment shown efficacious in adults with In the US, in 1997 the Food and drug Administration
similar processes. the only solution is to take all necessary (FdA) approved the first practical step to encourage the de-
measures and allocate sufficient resources to encourage velopment of medicines in children, the Food and drug Ad-
the development of medicines for children by conducting ministration Modernization Act (FdAMA, sec. 111), granted
randomised clinical trials (RCt) as well as pharmacody- a six month extensions of the patent protection vs. generics,
namic (Pd) and pharmacokinetic (PK) studies. if drugs already on the market were studied for use in chil-
dren. Moreover, since 2002, the Eunice Kennedy National
Difficulties for conducting neonatal clinical trials. Institute of Child Health and Human development (NICHd)
While solving the above problems would be to devel- of the NIH, periodically publishes lists of priorities for need-
op randomized clinical trials (RCt) in neonates, those are ed medications for children, that require more information.15
particularly difficult and expensive to conduct. drug devel- the European Medicine Agency (EMA, http://ema.europa.
opment is a complex process8 that requires collaboration eu) implemented similar measures to extend patents and
among different stakeholders: scientists, pharmaceutical in- publish an annual list of drugs to be developing for children
dustry, regulatory agencies, ethics committees, neonatolo- and neonates.16 In fact, it has gone a step further, because
gists and the final recipients of the process, patients, and in since 2007 recommended the inclusion of studies in chil-
the case of children, their parents or tutors. dren from the earliest stages of development of a new drug
the methodology used in the design and conduct of PK/ (http://eur-lex.europa.eu/lexUriServ/lexUriServ.do?uri=O
Pd in children is also complex. difficulties in patient recruit- J:l:2006:378:0001:0019:en:PdF)17 In addition, established
ment mandate the inclusion of as few babies as possible, a Paediatric Committee, which since July 2007 evaluates
to minimized pain and discomfort as well as the volume and Pediatric Research Plans (PIP) for the development of
number of biological samples. Empirical dosing extrapola- medicines in children. In fact, the presentation of the PIP is
tions from adults should be avoided. On the contrary, use mandatory for all new drugs that seek registration at Euro-
of prior knowledge in adults by using modeling and simu- pean level, or request to be excused if he had no indication
lation techniques might avoid unnecessary RCt.9. Another in this population.
difficulty is that all RCt in neonates most assess not only Moreover, the EMA has launched the European Net-
the immediate effects, but also long-term growth and neuro work of Paediatric Research (EnprEMA) form by accredited
A.V.S., E.S., M.M.: Neonatal Intensive Care and Neonatal Epidemiology Unit. Cruces University Hospital. University of the Basque country. Barakaldo-Bilbao. Spain.
Copyright © Ordem dos Médicos 2012
Revista Científica da Ordem dos Médicos 5 www.actamedicaportuguesa.com
3rd International Congress of UENPS 2012, Speakers, Acta Med Port 2012;25(S2):1-128 3rd International Congress of UENPS 2012, Speakers, Acta Med Port 2012;25(S2):1-128
European research networks in different pediatric subspe- Registry, including data for the last 10 years; and identified
cialties, including neonatology.17a the goal is to create the 77 completed RCt, 261 ongoing, 19 prematurely terminat-
necessary scientific and administrative competences to ed, and another 6 unauthorized. I think the record began
S
PE coordinate pediatric studies and avoid duplication of stud- in 2002 because it is the first date that leaves you select. A
A
K ies and testing in children. the EC has developed a Euro- similar search using the same term in the US registry identi-
E
RS pean registry of RCt, but not specific for pediatric studies fied 66 competed RCt, 1.585 either ongoing, without results
(https://www.clinicaltrialsregister.eu/), similar to that in the or lacking.
US (http://clinicaltrials.gov/). In addition, the EC has funded
a project to establish a specific record of RCt in children18 EuroNeoNet. A platform for clinical trials in neonates.
(http://www.dec-net.org/). A detailed review of regulation In conclusion, there is a notable absence of quality
of pediatric medications can be found at: http://www.ema. medicines especially developed to be both, effective and
europa.eu/docs/en_GB/document_library/Other/2009/09/ safe for its use in neonates, however currently it seems
WC500003693.pdf. to exist among the different stakeholders (patient organi-
Moreover, the 7th Research Framework Programme of zations, scientists, neonatologist, pharmaceutical industry
the European Commission (EC) has funded the European and regulatory agencies) a great concern and interest in
Clinical Research Infrastructures Network (ECRIN; http:// promoting and enhancing their development. three actions
www.ecrin.org/), which aims to promote and conduct mul- are proposed to enhance drug development in neonates at
ticenter multinational RCt at European level. In addition, European level:
this program supports projects to develop drugs that are 1. to maintain and even expand the Medicines for Children
included in the list published annually by the EMA. program of the EC, to provide specific and adequate public
Specifically, the EC made a public call to form a Network funding to study and develop common pediatric medicines
of Excellence for the promotion of medicines for children, without pediatric indication.
being selected and funded the project Global Research 2. to creating a European platform, to promote and per-
in Paediatrics (GRIP), which grew out of the project form RCt in neonates, at a European level. the EuroNeo-
tEddY19 .the GRIP project (http://www.grip-network.org) Net initiative - funded by dG SANCO since 2006 - has taken
involves 21 European institutions, and the WHO, the NICHd the strategic decision to do this, much as some national ini-
and the National Center for Child Health and development tiatives like the Medicines for Children Research Network
in Japan. the GRIP project was initiated in January 2011 by in England, Scotland, Holland and Belgium (http://www.
integrating 16 networks with hundreds of pediatric clinical rdlearning.org.uk/coursedetails.asp?Id=48350; http://www.
centers and a total of more than 1,000 researchers from scotmcn.org; http://www.mcrn.nl y http://www.pediatrie.be/
Europe, USA and Japan. GRIP has two primary missions. 1) pediatricdrug.htm).
develop a training program in Pediatric Clinical Pharmacol- 3. In addition, should be a European campaign to sensitize
ogy for pediatricians and other physicians, pharmacists and the public on the need for RCtin children, since the inclu-
pediatric nurses and 2) analyzed from every possible angle, sion in them is safer than being exposed to drugs that have
the constraints for the development of medicines for chil- not been tested in children and therefore of doubtful efficacy
dren. It also aims to validate and harmonize specific tools and security.
to carry out EC in Pediatrics, share strategies and plans Anyway, the solution to the problem of shortage of medi-
globally. due to its specificity, GRIP has a working group in cines for children should be global,20,21 by creating, as pro-
neonatology; co-direct the French pharmacologist Evelyne posed by the GRIP project, a truly international platforms of
Jacqz-Agrain and the first author of this paper; whose ob- pediatric pharmacology,22 able both to train professionals in
jectives include harmonizing the definitions used in neona- paediatric clinical pharmacology, and to facilitate the imple-
tal networks in terms of risk and protective factors, neonatal mentation of high quality, effective and safe drugs world-
interventions and main results. wide.23
Finally, we mention that the European Society for Paedi-
atric Research / European Society for Neonatology (ESPR/ AcKNoWLEdgEMENTS
ESN; http://www.espr.info/Pages/default.aspx) has been this work was supported in part by the Instituto de
included a Section on Pediatric and Neonatal Pharmacol- Salud Carlos III, Ministry of Economics, Spain, by grant
ogy, in order to promote the development of medicines for supporting the Research thematic Network on Maternal
children in Europe. and Child Health and development Network (Red SAMId,
to learn about the actual status of drug development Rd08/0072), and by the Global Research in Paediatrics
in neonates, we have performed a search using the terms Project (GRIP) of the EC’s 7th RFP (project No 261060).
Preterm Newborn and Newborn Infants in the European
REFERENcES
1. Peiré García MA. Importance of Clinical Pharmacology in Pediatrics. An 3. Stephenson t. How children’s responses to drugs differ from adults. Br
Pediatr 2010;72:99-102. J Clin Pharmacol 2005; 59:670-673.
2. Muro Brussi M. Clinical trials in children. New Royal decree, old con- 4. turner S, longworth A, Nunn AJ, Choonara I. Unlicensed and off la-
cepts. An Pediatr 2004;61:387-389. bel drug use in pediatric wards: prospective study. BMJ 1998;316:343-345.
Revista Científica da Ordem dos Médicos 6 www.actamedicaportuguesa.com
3rd International Congress of UENPS 2012, Speakers, Acta Med Port 2012;25(S2):1-128 3rd International Congress of UENPS 2012, Speakers, Acta Med Port 2012;25(S2):1-128
xxxxxxxxxxxxx 1901/2006). drugs for pediatric use and amending Regulation (EEC) No
5. Campino A, lopez-Herrera MC, lopez de Heredia I, Valls-i-Soler A. 1768/92,directive 2001/20/EC, directive 2001/83/EC and Regulation. EC No
Educational strategy to reduce medication errors in a neonatal intensive care 726/2004. Officer Journal European Union. 2006.
unit. Acta Paediatr 2009;98:782-785. 17. European Medicines Agency. Medicines for children. 26/01/2007. Ref RS
6. Conroy S. Association Between license status and medication errors. type: Online Source. KE
Arch dis Child 2011;96:305-306. a) 17a. Ruperto N, Eichler I, Herold , Giaquinto C, Hjorth l, Valls-i-Soler EA
7. Shirkey H. therapeutic orphans. J Pediatr 1968;72:119-120. A, Peters C, Helm PJ, Saint Raymond A. A European Network of Paediatric SP
8. Rocchi F, tomasi P. the development of medicines for children. Part of Research at the European Medicines Agency (Enpr-EMA). Arch dis Child
a series on Pediatric Pharmacology, guest edited by Gianvincenzo zuccotti, 2012; 97:185-188.
Emilio Clementi, and Massimo Molteni. Pharmacol Res 2011;64:169-175. 18. danish Carreras I, Fuentes Camps I, Arnau de Bolós JM, Pandolfini C,
9. Manolis E, Pons G. Proposals for model-based pediatric medicinal de- Bonati M, Sammons H, et al. A European register of clinical trials in children.
velopment Within the current European Union Regulatory Framework. Br J An Pediatr. 2004; 60:212-214.
Clin Pharmacol 2009;68:493-501. 19. Ceci A, Giaquinto C, Aboulker JP, Baiardi P, Bonifazi F, della PO, et
10. Chambers Cd, Polifka JE, Friedman JM. drug Safety in Pregnant Wom- al. the task-force in Europe for drug development for the Young (tEddY)
en and their Babies: Ignorance Not Bliss. Clin Pharmacol ther 2008;83:181- Network of Excellence. Paediatr Drugs. 2009; 11:18-21.
183. 20. Macleod S, Peterson R, Wang Y, li z, Gui Y, Schaller J. Challenges
11. Giacoia G, Mattison d. Obstetric and Fetal Pharmacology. Glob. libr. in international pediatric pharmacology: a milestone meeting in Shanghai.
Women’s Med. 2009. Paediatr Drugs. 2007; 9:215-218.
12. Mattison d, zajicek A. Gaps in knowledge in treating pregnant women. 21. Connor E, lombardi d, Van den Anker J. More than baby steps: per-
Gend Med 2006;3:169-182. spectives on pediatric translational research. Sci Transl Med 2009; 1:2 cm2.
13. Evans MI, Harrison MR, Flake AW, Johnson MP. Fetal therapy. Best 22. Knoppert d, Arenas-lopez S, McCartney R. the infancy of an interna-
Pract Res Clin Obstet Gynaecol. 2002; 16:671-683. tional pediatric network pharmacy. Paediatr Drugs. 2008; 10:71-73.
14. Noble R, Rodeck CH. Ethical considerations of fetal therapy. Best Pract 23. Arenas-lopez S, Fajardo C, Valls-i-Soler A, Garcia-Corzo JR, lima-
Res Clin Obstet Gynaecol. 2008; 22:219-231. Rogel MV, Calle G, leite R, lobos E, Hume-Wright Q, Macleord S. Pediatric
15. Collins FS. Best Pharmaceuticals for Children Act (BPCA) Priority list of clinical trials in latin America and Guyana: present views of local practition-
Needs in Pediatric therapeutics. Federal Register. 2011; 76:18228-18229. ers and ways to embrace the future. Paediatr drugs. 2011;1:257-265.
16. EC Regulation of the European Parliament nd and of the Council (No
Revista Científica da Ordem dos Médicos 7 www.actamedicaportuguesa.com
3rd International Congress of UENPS 2012, Speakers, Acta Med Port 2012;25(S2):1-128 3rd International Congress of UENPS 2012, Speakers, Acta Med Port 2012;25(S2):1-128
Management and Outcome of
S Extremely Low Birth Weight Infants
P
E
A
K
E
R
S
Apostolos Papageorgiou
Acta Med Port 2012;25(S2):8-9
INTRodUcTIoN
the mortality of extremely low birth weight infants further data is necessary before adoption of this method.
(ElBW) has decreased relentlessly during the past twenty For infants less than 1000 grams, it is recommended not to
years. At present, the limits of viability have been pushed as exceed the saturation of 92% and to keep the lowest pos-
low as 23 weeks of gestation in many countries and institu- sible inspiratory pressure, allowing some degree of permis-
tions. In terms of birth weight, the 500 grams baseline used sive hyperkapnea. Intravenous alimentation in most centers
until recent years has been replaced by 400 grams. is initiated on day one and trophic feeds in the first 48-72
In Canada, like in other industrialized countries, this hours of life. table 1 indicates our survival rates by gesta-
progress has been achieved thanks to the regionalization tional age and is the basis of our parental counselling. Our
of perinatal care, better understanding of the pathophysiol- institutional follow-up extends to the seventh year of age
ogy of the extremely immature infant, the administration of and includes physical and intellectual evaluation.
antenatal steroids and postnatal surfactant, the utilization of It is very important that data presented to the parents
intravenous alimentation and technological progress. on survival and potential complications should reflect insti-
However, although survival has much improved, the tutional epidemiological information and not general statis-
short and long term outcomes appear not to follow the same tics, because expertise and outcomes vary considerably
pattern of progress. Interventions at the limit of viability from one country to another and from one institution to the
(22-25 weeks of gestation) have generated heated debate other, as do medical, social, cultural and economic factors,
among professionals, parents and society at large, because Hence, a universal approach to the management of infants
of the clinical, ethical, economic and medico-legal implica- at the limits of viability is not a realistic proposition. Effective
tions. Significant differences in the criteria used for inter- communication between obstetrics, neonatology and par-
vention exist among neonatologists, countries and even ents can only prevent conflicts and suffering.
institutions within the same country. the Canadian guide- However, in spite of the significant progress, a number
lines consider fetuses equal or less than 22 weeks as non of serious questions regarding the interventions at the limits
viable. At 23 weeks and 24 weeks, the management is rec- of viability and their long term prognosis still await answers.
ommended to be tailored according to the parental wishes It is clear that more emphasis should be given now to the
after fully informed consultation. At 25 weeks of gestation, follow-up of these vulnerable infants and to their families
full support and Cesarean section, if indicated, is recom- once they leave the neonatal intensive care unit.
mended. Unfortunately, many of them do not get the appropriate
follow-up for early detection of deviations from normality nor
Medical Management the benefit of a multidisciplinary approach. Our follow-up
Significant changes have taken place in recent years studies indicate that their physical condition improves after
regarding the management of ElBW infants. Standards of the second year of life (table 2).
resuscitation and oxygenation have been significantly modi- Aside from the physical handicaps, a number of for-
fied. the use in the delivery Room of a pulse oxymeter has mer ElBW infants experience minimal brain dysfunction
facilitated avoidance of hypo or hyper oxygenation of the and school difficulties requiring special attention. However,
newborn. Although immediate use of CPAP is universally in spite all these difficulties, a significant number of them
practiced, less and less centers use automatic intubation manage to complete high school and university education.
and administration of surfactant in infants born less than 28 And, although as young adults they are more cautious,
weeks of gestation. However, early administration of surf- more shy, risk aversive, and less extraverted than their term
actant is recommended when oxygen requirements rapidly counterparts, in general, they appear to be satisfied with
exceed 40% despite CPAP. their health-related quality of life. In this context, the role of
Administration of surfactant with a feeding tube without the parents, their level of education and the available social
intubation has been recently promoted by some groups but support are essential factors which allow these children to
A.P.: Md, FRCPC, FAAP; Professor of Pediatrics, Obstetrics & Gynecology, McGill University; Chief of Neonatology, Jewish General Hospital, Montreal, Canada.
e mail: [email protected]
Copyright © Ordem dos Médicos 2012
Revista Científica da Ordem dos Médicos 8 www.actamedicaportuguesa.com
3rd International Congress of UENPS 2012, Speakers, Acta Med Port 2012;25(S2):1-128 3rd International Congress of UENPS 2012, Speakers, Acta Med Port 2012;25(S2):1-128
Table 1
GA (wks) Survival Minor handicaps Major handicaps
S
R
E
K
23 41% 40% 15-25% A
E
P
S
24 66% 30-35% 15%
25 84% 20-25% 5-10%
26 91% 10-15% 3-5%
table 2
MEdICAl HEAltH 22-25 wks GA
Need for rehospitalisation
0-24 months 2-5 years difference P value
30/53 (59%) 5/48 (10.5%) -44% 0.01
Medical Problems
Asthma 30/53 (59%) 15/48 (31%) -25 0.04
OM 28/53 (57%) 15/48 (31%) -25 0.06
attain the maximum of their potential. develop into adulthood in a satisfactory way. However, the
risks of school and developmental difficulties cannot be ig-
coNcLUSIoN nored, particularly for those born before 26 weeks of gesta-
Approaches to care and outcomes vary widely among tion. the need for close follow-up is essential and cannot be
centers and countries but overall, major progress has been overemphasized.
achieved in the survival of ElBW infants. Many of them
REFERENcES
1. Eichenwald E, Stark A. Management and outcomes of very low birth 4. Moster d et al. long term medical and social consequences of preterm
weight. NEJM 2008;358:1700-11. birth. NEJM 2008;359:262-73.
2. Neonatal Research Network. Early CPAP verus surfactant in extremely 5. Stephens B et al. Special health care needs of infants born at the limits
preterm infants. NEJM 2010;362:1970-9. of viability. Pediatrics 2010;125:1152-58.
3. Piuze G, Bardin C, Papageorgiou A. Growth and development at 5 6. Saigal S et al. Self-perceived health-related quality of life of for-
years of age of infants born between 22 and 25 weeks of gestation. Ped Res mer extremely low birth weight infants at young adulthood. Pediatrics
2000;47:45A. 2006;118:1140-8.
Revista Científica da Ordem dos Médicos 9 www.actamedicaportuguesa.com
3rd International Congress of UENPS 2012, Speakers, Acta Med Port 2012;25(S2):1-128 3rd International Congress of UENPS 2012, Speakers, Acta Med Port 2012;25(S2):1-128
Intrauterine growth Restriction:
S The Obstetrical Challenge and the Neonatal
P
E
A
K
E outcome
R
S
Apostolos Papageorgiou
Acta Med Port 2012;25(S2):10-11
INTRodUcTIoN
Intrauterine growth restriction (IUGR) is a common Following stabilization, a careful examination should be
complication in pregnancy that carries significant short and performed, as IUGR infants are a heterogeneous group.
long term sequellae that extend into adulthood. IUGR is the Some infants have obvious anomalies or syndromes and
second leading cause of perinatal mortality and morbidity others are born to mothers with known pathologies, i.e. pre-
after prematurity. Up to 53% of preterm and 26% of term eclampsia, chronic hypertension or social habits (smoking,
stillbirths are growth restricted and as many as 50% of sur- drug addiction, etc) and others present with classical signs
vivors will experience intrapartum asphyxia. of intrauterine infection (tORCH). However, for a number of
the terms IUGR and SGA are not synonymous. IUGR infants with IUGR, the etiology remains undetermined. Ma-
is due to a process that inhibits the normal growth poten- jor clinical complications requiring special attention: a post
tial of the fetus. SGA describes an infant whose weight is asphyxia syndrome with pulmonary hypertension, renal
lower than a predetermined cut-off weight (-2Sd, 5%, 10%). and gastrointestinal disturbances. Hypoglycemia, hypo-
Hence, all IUGR infants are not SGA. calcemia, polycythemia, thrombocytopenia and immuno-
the causes leading to IUGR and SGA infants are mul- logical disorders are also common complications and need
tiple, including genetic factors, infections or toxic factors, prompt attention.
maternal-social habits and placental dysfunction are among
the most important. Follow up of infants with IUgR
Because IUGR infants are a heterogeneous group, their
Incidence and importance of the problem potential for growth and development varies widely. the
In industrialized countries, 2.5-4% of all births and in worst prognosis is associated with chromosomal anom-
third World countries, 20-30% are growth restricted. Mor- alies, syndromes or first trimester intrauterine infection.
tality is 5-20, five times that of AGA and neurologic and the infants with symmetrical growth restriction have
other disorders 5-10 times that of AGA. the major cause of limited chance of postnatal catch up growth, where infants
mortality and morbidity is intrauterine or perinatal asphyxia, with late growth deceleration have reasonable potential for
as well as chromosomal or other anomalies. the extra-uter- catch up growth and normal development. Persistent hypo-
ine growth rate may be slower and catch up growth in some glycaemia has been associated with worse outcome. there
of them may never occur. is also a strong association between socio-economic fac-
tors and cognitive development and school performance of
Clinical diagnosis and management growth restricted children. Studies indicate that a number of
With modern management of pregnancies, IUGR can organs are affected in infants born with IUGR. For instance,
be diagnosed and followed up with repeat ultrasound, BPP adolescent girls have small uteri (mean difference 20%, P
and doppler studies. the real challenge for the obstetrical value <0.006) and reduced ovarian growth (mean differ-
perinatologists is to establish a precise diagnosis of the eti- ence 38%, p <0.0002). Also studies on vascular relaxation
ology of IUGR and decide on the time and type of delivery. indicate signs of endothelial dysfunction at birth, as dem-
For the neonatologist, it is important to rapidly recognize onstrated by the response of skin perfusion to injection of
the presence of chromosomal or other anomalies respon- acetylcholine. the perfusion increases by 240% in IUGR vs
sible for the growth restriction and also establish whether 650% in AGA infants.
the infant is symmetrically or asymmetrically (head sparing) Autopsy of the brain in infants with IUGR has shown
affected because of the different short and long term prog- restriction in myelination and decreased frontal cortical syn-
nosis aptogenesis. In that respect it is important to appreciate
Infants with IUGR can present at birth with a variety that primary visual cortex has a critical period of neuronal
of problems in the delivery room. It is important to ensure dendritic differentiation during mid-gestation. Preferential
optimal cardio-respiratory support and avoid heat loss. perfusion of the fetal brain is favourable for intact gross
A.P.: Md, FRCPC, FAAP; Professor of Pediatrics, Obstetrics & Gynecology, McGill University; Chief of Neonatology, Jewish General Hospital, Montreal, Canada.
e mail: [email protected]
Copyright © Ordem dos Médicos 2012
Revista Científica da Ordem dos Médicos 1 0 www.actamedicaportuguesa.com