Long Term Effects NICU Medications

Long term
sequelae of NICU
medications
By M Osama Hussein, MD
Neonatology consultant,
Port Said, EGYPT

 One of the hardest
things for a parent is to
watch their child be
sick, and that difficulty
is only amplified when
their little patient is a
newborn who’s landed
in a neonatal intensive
care unit (NICU).

CNS
 Recent clinical trial from
an Australian birth cohort
suggests a single
anesthesia exposure as
a neonate or infant may
increase the risk for
language and abstract
reasoning deficits later in
life. Olsen & Brambrink,
2013.
Anesthesia
 Recent clinical trial from
an Australian birth cohort
suggests a single
anesthesia exposure as
a neonate or infant may
increase the risk for
language and abstract
reasoning deficits later in
life. Olsen & Brambrink,
2013.

CNS
 The rule of sub cellular
organelles, such as
mitochondia, in the
pathophysiology of
neonatal anesthesia
exposure was recently
revealed. Forcelli, 2015.
Anesthesia
 The rule of sub cellular
organelles, such as
mitochondia, in the
pathophysiology of
neonatal anesthesia
exposure was recently
revealed. Forcelli, 2015.

Antiepileptic
 The Neurodevelopmental
Effects of Antiepileptic
Drugs were studied to
determine if differential
long-term effects exist
across four commonly
used AEDs
(carbamazepine,
lamotrigine, phenytoin,
and valproate). Cohen et
al, 2013.
 The Neurodevelopmental
Effects of Antiepileptic
Drugs were studied to
determine if differential
long-term effects exist
across four commonly
used AEDs
(carbamazepine,
lamotrigine, phenytoin,
and valproate). Cohen et
al, 2013.

Antiepileptic
 Adaptive Behavior
Assessment System-
Second Edition (ABAS-II)
was in the low average
level
 Emotional/behavioral
functioning on the
Behavior Assessment
System for Children
(BASC) was also in the low
average level.
 Adaptive Behavior
Assessment System-
Second Edition (ABAS-II)
was in the low average
level
 Emotional/behavioral
functioning on the
Behavior Assessment
System for Children
(BASC) was also in the low
average level.

Antiepileptic
 Valproate during
pregnancy had
significantly lower General
Adaptive Composite
scores than the
lamotrigine
and phenytoin groups.
 Valproate during
pregnancy had
significantly lower General
Adaptive Composite
scores than the
lamotrigine

Antiepileptic
 A significant dose-related
performance decline in
adaptive functioning was
seen for both valproate
and phenytoin.
 A significant dose-related
performance decline in
adaptive functioning was
seen for both valproate
and phenytoin.

Antiepileptic
 Children whose mothers
took valproate had
significantly more atypical
behaviors and inattention
than those in the
lamotrigine
 Children whose mothers
took valproate had
significantly more atypical
behaviors and inattention
than those in the
lamotrigine

Antiepileptic
 Based upon BASC parent
and teacher ratings of
attention span and
hyperactivity, children of
mothers who took
valproate during their
pregnancy were at a
significantly greater risk
for a diagnosis of ADHD.
Cohen et al, 2013.
 Based upon BASC parent
and teacher ratings of
attention span and
hyperactivity, children of
mothers who took
valproate during their
pregnancy were at a
significantly greater risk
for a diagnosis of ADHD.
Cohen et al, 2013.

Sedatives & analgesics
 In 348 neonatal intensive
care units, 31 % of
deceased received a
sedative or analgesic till
the day of death; opioids
were most frequently
administered, (27%).
 In 348 neonatal intensive
care units, 31 % of
deceased received a
sedative or analgesic till
the day of death; opioids
were most frequently
administered, (27%).

 Increasing gestational age,
increasing postnatal age,
invasive procedure within 2
days of death, more recent
year of death, mechanical
ventilation, inotropic
support, and antibiotics on
the day of death were
associated with exposure
to sedatives or analgesics.
 Increasing gestational age,
increasing postnatal age,
invasive procedure within 2
days of death, more recent
year of death, mechanical
ventilation, inotropic
support, and antibiotics on
the day of death were
associated with exposure
to sedatives or analgesics.

 Administration of opioids
and benzodiazepines
increased during the
study period that may be
driven by severity of
illness. Zimmerman et al,
J Pediatrics, 2015
 Administration of opioids
and benzodiazepines
increased during the
study period that may be
driven by severity of
illness. Zimmerman et al,
J Pediatrics, 2015

 Almost half of the
neonates admitted to
intensive care units
receive sedatives or
analgesics in a study
conducted in 30 Spanish
neonatal units. Alvarez et
al, 2015
 Almost half of the
neonates admitted to
intensive care units
receive sedatives or
analgesics in a study
conducted in 30 Spanish
neonatal units. Alvarez et
al, 2015

 At 5-7 years of age,
neuropsychological
outcomes,
morphometrics, adaptive
behavior, parent-rated
behavior, motivation, and
short-term memory were
measured in NICU
graduates who were given
Morphia as analgesic.
 At 5-7 years of age,
neuropsychological
outcomes,
morphometrics, adaptive
behavior, parent-rated
behavior, motivation, and
short-term memory were
measured in NICU
graduates who were given
Morphia as analgesic.

 The overall IQ and academic
achievement did not differ
between the morphine &
placebo groups, but head
circumference
of morphine treated children
was approximately 7%
smaller & body weight was
approximately 4% less
 The overall IQ and academic
achievement did not differ
between the morphine &
placebo groups, but head
circumference
of morphine treated children
was approximately 7%
smaller & body weight was
approximately 4% less

 The short-term memory
task, morphine treated
children exhibited
significantly longer choice
response latencies than
placebo children.
 The short-term memory
task, morphine treated
children exhibited
significantly longer choice
response latencies than
placebo children.

 Morphine treated children
had more social problems.
 These results are strongly
suggestive of long-lasting
effects of
preemptive morphine analge
sia.
Ferguson et al, 2013
 Morphine treated children
had more social problems.
 These results are strongly
suggestive of long-lasting
effects of
preemptive morphine analge
sia.
Ferguson et al, 2013

 In very preterm children who
undergo mechanical
ventilation, morphine is
important, yet morphine may
adversely affect internalizing
behaviours at school age.
Rangers et al, 2014
 In very preterm children who
undergo mechanical
ventilation, morphine is
important, yet morphine may
adversely affect internalizing
behaviours at school age.
Rangers et al, 2014

 Repeated morphine
administration during the
neonatal period followed by re-
exposure to morphine
produces considerable
anxiolytic-like behaviour.
Gholami et al, 2014
 Repeated morphine
administration during the
neonatal period followed by re-
exposure to morphine
produces considerable
anxiolytic-like behaviour.
Gholami et al, 2014

 Midazolam should be
avoided in preterm
neonates, due to the
concerning incidence of
brain injury in randomized
trial.
McPherson, 2012
 Midazolam should be
avoided in preterm
neonates, due to the
concerning incidence of
brain injury in randomized
trial.
McPherson, 2012

 Parenteral fentanyl might
have lasting growth and
behavioral changes when
used as an analgesic in
neonatal period. Catre et al,
2012
 Parenteral fentanyl might
have lasting growth and
behavioral changes when
used as an analgesic in
neonatal period. Catre et al,
2012

 It has been shown that SMX-
TMP does not directly cause
neonatal kernicterus, yet it
does not rule out any other
toxicity that could be caused
by SMX-TMP.
Thyagarajan and Deshpand
e, 2014
Sulfamethoxazole Trimethoprim
 It has been shown that SMX-
TMP does not directly cause
neonatal kernicterus, yet it
does not rule out any other
toxicity that could be caused
by SMX-TMP.
Thyagarajan and Deshpand
e, 2014

 Caffeine is the preferred
first-line of treatment of AOP
with less adverse events
compared to theophylline.
Yet RCTs are needed to
assess the safety and
efficacy of high-dose
caffeine especially on long-
term neurodevelopmental
outcomes. Abdel Hady et al,
2015
Caffeine citrate
 Caffeine is the preferred
first-line of treatment of AOP
with less adverse events
compared to theophylline.
Yet RCTs are needed to
assess the safety and
efficacy of high-dose
caffeine especially on long-
term neurodevelopmental
outcomes. Abdel Hady et al,
2015

 HC exposure for >7 days is
associated with worse
performance in fine motor skills
in the first year of life, while
cumulative HC exposure
negatively impacts receptive
and expressive language skills
in the first year and motor skills
in the second year of life . Patra
et al, 2015
Hydrocortisone

 Long- term
amiodarone exposure (for
SVT & junctional
reciprocating tachycardia
treatment ) was indirectly
related to
neurodevelopmental
delay. Mikovic et al, 2010
Amiodarone

 Since the late 1980s
recombinant human
erythropoietin (r-Epo) has
been studied as an
alternative to packed red
blood cell (RBC) transfusion
for the treatment of anemia
of prematurity in very low
birth weight (VLBW, <1500
grams) infants
Eye

 It was found that early EPO
administration improves
white matter development in
preterm infants. Gorman et
al, 2015
 It was studied as one of new
therapeutic modalities for
hypoxic-ischemic
encephalopathy. Rogers et
al, 2015

Eye

 In a Cochrane review it was
stated that a statistically
significant increased risk of
ROP (any grade) and a
similar trend for ROP
stage > 3 was found with
EPO use especially when
early administered. Aher &
Ohlsson. Cochrane Neonatal
Group, 2013
Eye

 Eur J Pediatr. meta-analysis
indicated that
EPO treatment is not
associated with the
development of ROP in
preterm infants. Xu et al, 2014
Eye

 A retrospective study was
published in the Eye journal
performed in the Department of
Neonatology, Townsville
Hospital, North Queensland in
688 preterm neonates, it was
stated that EPO therapy
appears to increase the risk of
development and worsening of
ROP. Kandasamy et al, 2014
Eye

GIT
 drugs containing sodium
alginate have been linked
to bezoar formation and
to adverse events due
aluminum’s toxicity.
Sorbie et al, 1984
Tsou et al,1991.
Klish et al, 1996.

GIT
 Na alginate treatment for
gastroesophageal reflux
disease
in preterm infants seem
to be safe and effective.
Atasay et al, 2010.

GIT
 Ranitidine therapy is
associated with an
increased risk of
infections, NEC, and fatal
outcome in VLBW
infants. Caution is
advocated in the use of
this drug in neonatal age.
Canani, 2012.

AZITHROMYCIN & ERYTHROMYCIN
 Ingestion of
oral azithromycin and
erythromycin places young
infants at increased risk of
developing infantile
hypertrophic pyloric stenosis
IHPS.

AZITHROMYCIN & ERYTHROMYCIN
 This association is strongest
if the exposure occurred in
the first 2 weeks of life, but
persists although to a lesser
degree in children between 2
and 6 weeks of age
Eberly et al 2015

Cardiac
 prokinetic agents, such
as domperidone was
used cautiously lately,
whereas cisapride has
been withdrawn due to
its remarkable cardiac
adverse effects.
Corvaglia et al, 2013.

Cardiac
 Despite the widespread
use of β2-agonists,
their safety has been
questioned.

Cardiac
 Several studies have
reported an increased
incidence of cardiac
arrhythmias in patients
treated with these
agents.

Cardiac
 Other studies have found
increased rates of
cardiovascular death
associated with the use
of oral and nebulized β2-
agonists such
as salbutamol.
Corvaglia et al, 2013.

Cardiac
 Furosemide use in the
preterm carries the risk
of precipitation of
symptomatic patent
ductus arteriosus.
Pacifici et al, 2013.

Cardiac
 Furosemide should be
used cautiously in
preterm babies to avoid
the risk of keeping the
ductus patent.
Abdel Hady et al, 2013.

Cardiac
 Elective administration of
furosemide to any patient
with RDS should be
carefully weighed against
the risk of precipitating a
symptomatic PDA.
Cochrane review, 2011.

Prostaglandin E1 Alprostadil
 Aneurysmal dilatations of
ductus & pulmonary
arteries.
 Cerebral bleeding
 Gastric outlet obstruction
secondary to antral
hyperplasia, yet it’s
mostly transient. Soyer et
al, 2014
 Aneurysmal dilatations of
ductus & pulmonary
arteries.
 Cerebral bleeding
 Gastric outlet obstruction
secondary to antral
hyperplasia, yet it’s
mostly transient. Soyer et
al, 2014

Endocrinal system
 Especially in
girls, neonatal
dexamethasone has a
programming effect on the
hypothalamus-pituitary-
adrenal-axis and on the
ability to adjust to the
environment. Wolbeek et
al, 2015
 Especially in
girls, neonatal
dexamethasone has a
programming effect on the
hypothalamus-pituitary-
adrenal-axis and on the
ability to adjust to the
environment. Wolbeek et
al, 2015

Renal sequelae of neonatal
medications
Acute kidney injury is associated with high mortality in
preterm neonates. It is very important to identify, as quickly
as possible, all infants who are at high risk of developing
AKI. Stojanović et al, 2014

Aminoglycosides
Gentamicin is probably the most studied drug- nephrotoxin

Aminoglycosides
Nephrotoxicity
gentamicin > tobramycin > amikacin > netilmicin

Aminoglycosides
Amikacin have an ototoxic effect that’s dose-dependent.
Preterm infants are especially susceptible. Engler et al, 2013
Amikacin have an ototoxic effect that’s dose-dependent.
Preterm infants are especially susceptible. Engler et al, 2013

Aminoglycosides
Other risk factors: prolonged therapy, malnutrition,
volume depletion, liver disease, preexisting renal
disease, K and Mg depletion. Girardi et al, 2015

Aminoglycosides
Other risk factors: concomitant exposure to other
nephrotoxic drugs such as amphotericin B, ciclosporin,
vancomicin and NSAIDs. Girardi et al, 2015

Glycopeptides
Vancomycin is one of nephrotoxic antimicrobials used
frequently in NICU. Bhongsatiern et al, 2015

Glycopeptides
Teicoplanin was reported to cause nephrotoxicity yet
when dose is closely monitored it can be used safely in
neonates. Yamada et al, 2014
Teicoplanin was reported to cause nephrotoxicity yet
when dose is closely monitored it can be used safely in
neonates. Yamada et al, 2014

Beta-Lactams Cephalosporins
Cephaloridine and cephaloglycine are the only
cephalosporins capable of causing kidney damage
(involving the mitochondria) at therapeutic doses.
Roberts et al, 2014
Cephaloridine and cephaloglycine are the only
cephalosporins capable of causing kidney damage
(involving the mitochondria) at therapeutic doses.
Roberts et al, 2014

Beta-Lactams Cephalosporins
For all the other cephalosporins the renal damage can
occur only at extremely high doses, much greater than
the routine therapeutic doses. Roberts et al, 2014
For all the other cephalosporins the renal damage can
occur only at extremely high doses, much greater than
the routine therapeutic doses. Roberts et al, 2014

Antibiotic NICU use recommendations
Considerable inter-centre variability of dosage
regimens of antibiotics exists in NICUs.

Antibiotic NICU use recommendations
Developmental pharmacokinetic–pharmacodynamic
studies are essential to establish evidence-based
dosage regimens for effective and safe administration
in neonates. Leroux et al, 2014
Developmental pharmacokinetic–pharmacodynamic
studies are essential to establish evidence-based
dosage regimens for effective and safe administration
in neonates. Leroux et al, 2014

Antifungals Amphotericin B
A nephrotoxic antifungal that’s widely replaced by the
less toxic other antifungals. Rhone et al, 2013

Antifungals Amphotericin B
The azoles (itraconazole, fluconazole, voriconazole),
the fluorinated pyrimidines (flucytosine), the
echinocandins (caspofungin, micafungin, anidulafungin
are much better tolerated Rhone et al, 2013
The azoles (itraconazole, fluconazole, voriconazole),
the fluorinated pyrimidines (flucytosine), the
echinocandins (caspofungin, micafungin, anidulafungin
are much better tolerated Rhone et al, 2013

Nonsteroidal Antiiflammatory Drugs
(NSAIDS)
The nephrotoxic effects of NSAIDs are related to their
mechanism of action: block of prostaglandin synthesis
with the inhibition of cyclooxygenase (COX) enzymes.
Xavier et al, 2010

(NSAIDS)
For many years indomethacin has been the drug of
choice in the treatment and prophylaxis of PDA in
premature neonates. Xavier et al, 2010

(NSAIDS)
Ibuprofen has been shown to close successfully the
ductus arteriosus in animals and newborns without
affecting renal hemodynamics. Xavier et al, 2010

(NSAIDS)
Indomethacin is associated with more severe renal
adverse effects than ibuprofen. Immaturity increases
the frequency of adverse effects of indomethacin.
Pacifici, 2013
Indomethacin is associated with more severe renal
adverse effects than ibuprofen. Immaturity increases
the frequency of adverse effects of indomethacin.
Pacifici, 2013

Furosemide
Infants with low birthweight treated with chronic
furosemide are at risk for the development of intra-
renal calcifications. Pacifici, 2013
Infants with low birthweight treated with chronic
furosemide are at risk for the development of intra-
renal calcifications. Pacifici, 2013

Antifungal (Fluconazole)
 Fluconazole have to be
used cautiously since it
may affect renal function
& raise transaminases.
Its rule as a prophylaxis
in premies was criticized.
Benjamine, 2014
 Fluconazole have to be
used cautiously since it
may affect renal function
& raise transaminases.
Its rule as a prophylaxis
in premies was criticized.
Benjamine, 2014

Antifungal (Fluconazole)
 Few cases were
presented with Toxic
epidermal necrolysis due
to fluconazole use in
NICU. Islam et al, 2014
 Few cases were
presented with Toxic
epidermal necrolysis due
to fluconazole use in
NICU. Islam et al, 2014

Antiviral (Acyclovir)
 Renal dysfunction with
increasing urea and
creatinine – risk increased
by dehydration, bolus
injection or other
nephrotoxic drugs.
Zappitelli et al, 2012

Vitamin D toxiciy
 Vitamin D intoxication with
severe hypercalcemia is
rare in the neonatal and
infancy period & is related
mostly to overdosage but a
mechanisms of
hypersensitivity was also
reported. Hmami et al, 2014
 Vitamin D intoxication with
severe hypercalcemia is
rare in the neonatal and
infancy period & is related
mostly to overdosage but a
mechanisms of
hypersensitivity was also
reported. Hmami et al, 2014

Angiotensin converting enzyme (ACE)
inhibitors
 1 % of NICU patients were
found to suffer hypertension
and those are usually treated with
vasodilators (64.2%),
ACE inhibitors (50.8%),
calcium channel blockers
(24%), and alpha- and
beta-blockers (18.4%).
Blowey et al, 2011
 1 % of NICU patients were
found to suffer hypertension
and those are usually treated with
vasodilators (64.2%),
ACE inhibitors (50.8%),
calcium channel blockers
(24%), and alpha- and
beta-blockers (18.4%).
Blowey et al, 2011

inhibitors
 Renal impairment was
documented with Captopril
use in neonates and was
not dose related but
reversible.
Gantenbein et al, 2008
 Renal impairment was
documented with Captopril
use in neonates and was
not dose related but
reversible.
Gantenbein et al, 2008

inhibitors
 Neonates treated with
enalapril for either
hypertension or for a
cardiac disorder were
found to suffer a potential
renal impairment .
Russo et al, 2013
 Neonates treated with
enalapril for either
hypertension or for a
cardiac disorder were
found to suffer a potential
renal impairment .
Russo et al, 2013

inhibitors
 The premature neonates are
more likely to experience
ACEi-related renal failure than
their term counterparts .
Lindle et al, 2014
 The premature neonates are
more likely to experience
ACEi-related renal failure than
their term counterparts .
Lindle et al, 2014

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Long Term Effects NICU Medications

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