long term sequelae of nicu medications

Long term sequelae of

NICU medications

By M Osama Hussein, MDNeonatology 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 and phenytoin groups.

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 and phenytoin groups.

Children whose mothers took valproate had significantly more atypical behaviors and inattention than those in the lamotrigine and phenytoin groups.

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%).

Sedatives & 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.

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.

Sedatives & 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

Sedatives & analgesics 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

Sedatives & analgesics 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

Sedatives & analgesics 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.

Sedatives & analgesics 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 analgesia.

Ferguson et al, 2013

Sedatives & analgesics Morphine treated

children had more social problems.

These results are strongly suggestive of long-lasting effects of preemptive morphine analgesia.

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

Sedatives & analgesics 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

Sedatives & analgesics 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

Sedatives & analgesics 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

Sedatives & analgesics Parenteral fentanyl might

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

Sedatives & analgesics

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 Deshpande, 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 Deshpande, 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

Nephrotoxicitygentamicin > 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


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


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


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


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


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


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

Osama Hussein

long term sequelae of nicu medications

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