This project aims to develop an evidence based effective and "safe" dosing regimen for commonly used life saving medicationsused in the treatment of asphyxiated, critically ill newborns, undergoing therapeutic hypothermia.To this aim the…
ID
Source
Brief title
Condition
- Congenital and peripartum neurological conditions
- Neonatal and perinatal conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary study outcomes:
1) PK properties of three groups of drugs in a prospective cohort of patients:
Group I: Antibiotic medications
Group II: Analgesic medications
Group III:Sedative and anti-epileptic drugs
2) PD parameters :
-anti-epileptic drugs: successful seizure control (anti-epileptics),
-sedative drugs: measuring newborn stress using the Comfort Scale.
-antibiotics: adequate treatment of perinatal infection shown by negative
repeat blood culture, normalisation of C-reactive protein and leukocyte counts
(antibiotics),
- determination of the MIC -value of cultured microorganisms to evaluate
antibiotic susceptibility -or resistance.
3) possible side effects:(e.g. gentamyxcin)
-(acute) drug effects on end organs such as liver, kidney, bone marrow,
-(long-term outcome) hearing screening at 3 months of age including the ALGO
newborn hearing screening.
Secondary outcome
FOLLOW-UP
Long term follow-up in these asphyxiated neonates is part of the standard care
protocol of the Dutch Working Group of Neonatal follow-up (L.N.F.). Data are
collected outside the scope of this project. Long term outcome by
neurodevelopmental testing at the ages of 6 months, 1 and 2 years will be
related to neonatal pharmacological and clinical data.
Background summary
Perinatal asphyxia resulting in hypoxic ischemic encephalopathy (HIE) occurs in
1-2 infants per 1000 deliveries.. Term neonates experiencing a severe
hypoxic-ischemic insult during birth may develop HIE within hours. There is a
high risk for long term neurological sequelae as cerebral palsy, psychomotor
retardation or visual or auditory handicaps
CONCEPT
Supportive treatment comprises mechanical ventilation, cardiovascular support,
and treatment of infections and seizures. The most frequently used life-saving
drugs in these cases are sedatives, analgesics, antibiotics, and antiepileptic
drugs (AED).
CONTROLLED HYPOTHERMIA
The standard treatment for HIE is aimed at stabilisation of physiological vital
parameters and detection and management of neonatal seizures. Recent large
randomized controlled trials in human asphyxiated neonates demonstrated a
statistically significant and clinically important improvement of long term
outcome. Maximum benefit of hypothermia is attained when this
treatment is initiated within six hours following the perinatal hypoxic
ischemic event. Since 2009, all 10 Neonatal Intensive Care Units (NICUs) in the
Netherlands have adopted controlled hypothermia as the standard of care in
neuroprotection for neonates with HIE.
PHARMACOTHERAPY AND THERAPEUTIC HYPOTHERMIA
PK/PD properties of commonly used drugs in neonatal intensive care are
influenced by hypothermia. Unknown Pharmacokinetics may also result in
subtherapeutic drug dosing. Since each year 200 newborns will be exposed to
controlled hypothermia in the Netherlands, the development of evidence based
guidelines concerning drug dosing (including loading dose and dose interval)
and therapeutic drug monitoring are urgently needed.
This study has been prioritized by the NNRN and is featured in the top 5 of the
Research Agenda 2009-2011 of the MCRN.
Study objective
This project aims to develop an evidence based effective and "safe" dosing
regimen for commonly used life saving medicationsused in the treatment of
asphyxiated, critically ill newborns, undergoing therapeutic hypothermia.
To this aim the PK/PD properties of three groups of drugs will be investigated
in a prospective cohort of patients:
Group I: Antibiotic medications: Penicillin; Amoxycillin; Gentamycin; Amikacin;
Vancomycin; Ceftazidim
Group II: Analgesic medications: Morphine
Group III:Sedative and anti-epileptic drugs: Midazolam; Phenobarbitone;
Lidocaine
After the translation of results into dosing regimens tailored to this patient
group these regimens will be implemented in all Dutch NICUs.
Study design
Multicenter nationwide prospective cohort study in 10 NICUs treating
asphyxiated newborns with controlled hypothermia in which plasma levels of
antiepileptic, sedative and antibiotic drugs will be measured and used for PK
analysis to develop rational and safe
dosage regimens. As a secondary outcome measure the association of possible
toxic drug levels with long term clinical outcome will be investigated.
Study burden and risks
The patient burden consists of additional bloodsampling for PKPD research.
In total maximally 7 ml will be taken from the bloodstream by indwelling
arterial line catheters that are in place in all patients. No extra
venapunctures will be performed for this research.
As the average birth weight of a term newborn is 3.5 kg and the circulating
blood volume is 80 ml/ kg (total blood volume: 280 ml), 7 ml will comprise only
2.5% of the total circulating volume for this whole study. A mean volume of
only 0.7% of the total circulating blood volume will thus be taken each day for
PK/PD research. This is clinically entirely acceptable in terms of circulatory
compromise or risk for anemia.
Blood samples for PKPD research will be taken together with clinically
indicated blood sampling. Central (arterial) lines will provide bloodstream
access for blood sampling. If these lines are not functioning or cannot be
placed, infants can not participate in this study.
meibergdreef 9
1100DD Amsterdam
NL
meibergdreef 9
1100DD Amsterdam
NL
Listed location countries
Age
Inclusion criteria
Any newborn :;1) with a gestational age > 36 weeks and a birth weight > 3 kg;
2) with Apgar Score at 5 minutes postnatal < 5;
3) with continued resuscitation at 10 minutes postnatally;
4) with 1 hour postnatal bloodgas analysis with pH < 7.0 or base deficit > 16
5) with clinical signs of moderate to severe encephalopathy (defined as a Thomson score of >7 or a Sarnat score of >1)
6) who is undergoing neuroprotective treatment by controlled hypothermia < 6 hours postnatally.
Exclusion criteria
1) congenital hepatic or renal pathology (as this makes interpretation of PKPD results impossible);
2) without central venous line or arterial bloodstream access for blood sampling;
3) without written parental consent to participate following informed consent interview.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL32724.018.10 |