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Long term sequelae of nicu medications

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A 100 years ago, when neonatal intensive care units (NICUs) started to be well established, the race never stopped trying to add new regimens to improve neonatal survival. On the other hand, long term sequelae of medications used at NICUs were usually not sufficiently studied and left mostly unnoticed for many years by neonatologists. Here we are trying to understand & & shed the light on some of these sequelae in a trial avoid those sequelae while working on NICU candidates.
Lecture given at the 6th Conference for Nile Basin Pediatrics 2-5 December 2015, Hurgada, Egypt

Published in: Health & Medicine

Long term sequelae of nicu medications

  1. 1. Long term sequelae of NICU medications By M Osama Hussein, MD Neonatology consultant, Port Said, EGYPT
  2. 2.  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).
  3. 3. 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.
  4. 4. 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.
  5. 5. 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.
  6. 6. 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.
  7. 7. 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.
  8. 8. 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.
  9. 9. 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.
  10. 10. 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.
  11. 11. 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%).
  12. 12. 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.
  13. 13. 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
  14. 14. 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
  15. 15. 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.
  16. 16.  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
  17. 17.  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.
  18. 18.  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 Sedatives & analgesics  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
  19. 19.  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
  20. 20.  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
  21. 21.  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
  22. 22.  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
  23. 23. Sedatives & analgesics
  24. 24.  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
  25. 25.  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
  26. 26.  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
  27. 27.  Long- term amiodarone exposure (for SVT & junctional reciprocating tachycardia treatment ) was indirectly related to neurodevelopmental delay. Mikovic et al, 2010 Amiodarone
  28. 28.  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
  29. 29.  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
  30. 30.  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
  31. 31.  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
  32. 32.  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
  33. 33. 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.
  34. 34. GIT  Na alginate treatment for gastroesophageal reflux disease in preterm infants seem to be safe and effective. Atasay et al, 2010.
  35. 35. 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.
  36. 36. AZITHROMYCIN & ERYTHROMYCIN  Ingestion of oral azithromycin and erythromycin places young infants at increased risk of developing infantile hypertrophic pyloric stenosis IHPS.
  37. 37. 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
  38. 38. 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.
  39. 39. Cardiac  Despite the widespread use of β2-agonists, their safety has been questioned.
  40. 40. Cardiac  Several studies have reported an increased incidence of cardiac arrhythmias in patients treated with these agents.
  41. 41. 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.
  42. 42. Cardiac  Furosemide use in the preterm carries the risk of precipitation of symptomatic patent ductus arteriosus. Pacifici et al, 2013.
  43. 43. Cardiac  Furosemide should be used cautiously in preterm babies to avoid the risk of keeping the ductus patent. Abdel Hady et al, 2013.
  44. 44. 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.
  45. 45. 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
  46. 46. 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
  47. 47. 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
  48. 48. Aminoglycosides Gentamicin is probably the most studied drug- nephrotoxin
  49. 49. Aminoglycosides Nephrotoxicity gentamicin > tobramycin > amikacin > netilmicin
  50. 50. 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
  51. 51. Aminoglycosides Other risk factors: prolonged therapy, malnutrition, volume depletion, liver disease, preexisting renal disease, K and Mg depletion. Girardi et al, 2015
  52. 52. Aminoglycosides Other risk factors: concomitant exposure to other nephrotoxic drugs such as amphotericin B, ciclosporin, vancomicin and NSAIDs. Girardi et al, 2015
  53. 53. Glycopeptides Vancomycin is one of nephrotoxic antimicrobials used frequently in NICU. Bhongsatiern et al, 2015
  54. 54. 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
  55. 55. 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
  56. 56. 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
  57. 57. Antibiotic NICU use recommendations Considerable inter-centre variability of dosage regimens of antibiotics exists in NICUs.
  58. 58. 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
  59. 59. Antifungals Amphotericin B A nephrotoxic antifungal that’s widely replaced by the less toxic other antifungals. Rhone et al, 2013
  60. 60. 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
  61. 61. 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
  62. 62. Nonsteroidal Antiiflammatory Drugs (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
  63. 63. Nonsteroidal Antiiflammatory Drugs (NSAIDS) Ibuprofen has been shown to close successfully the ductus arteriosus in animals and newborns without affecting renal hemodynamics. Xavier et al, 2010
  64. 64. Nonsteroidal Antiiflammatory Drugs (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
  65. 65. 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
  66. 66. 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
  67. 67. 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
  68. 68. Antiviral (Acyclovir)  Renal dysfunction with increasing urea and creatinine – risk increased by dehydration, bolus injection or other nephrotoxic drugs. Zappitelli et al, 2012
  69. 69. 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
  70. 70. 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
  71. 71. Angiotensin converting enzyme (ACE) 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
  72. 72. Angiotensin converting enzyme (ACE) 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
  73. 73. Angiotensin converting enzyme (ACE) 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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