Norliza Mat Ariffin Clinical Pharmacist Selayang Hospital

The Premature Infant : < 37 weeks gestation Low birth weight : <2.5kg VLBW : <1.5kg ELBW : <1kg Small of gestational age : SGA * Peadiatric protocol for Malaysian Hospitals, 2nd Edition.

TERM : Respiratory distress syndrome (pneumonia, TTN, meconium aspiration), infant of diabetec mother, sepsis. PRETERM : RDS, patent ductus arteriosus, necrotizing of enterocolitis, sepsis

RDS or HMD (hyaline membrane disease) Incidence : 14-50% ( 24-34 weeks gestation) Risk factor : premature, male, elective ceasarean & maternal diabetes

Surfactant deficiency or dysfunction Surfactant : dipamitoylphosphatidylcholine + other phospholipids. Indications of surfactant: Early rescue therapy (treatment) confirmed by xray and requiring mechanical ventilation

Benefits: 1. improves survival, reduced pneumothorax, intraventricular haemorhage 2. early (before 2 hours) : reduced mortality & chronic lung disease

Natural ( eg Survantae, Curosurf) vs synthetic (Exosurf) Natural : greater early improvement, shorter ventilatory support, less air leak Dosing : Survantae (4ml/lg; 100mg phospholipids/kg) Method : intra-intracheal Administration : First dose on less than 2 hours of life & 2nd dose if necessary 6 hours later from initial dose, 4ml/kg

It is a general term for longterm respiratory problems in premature babies. It is also known as bronchopulmonary dysplasia (BPD).

CLD results from lung injury to newborns who must use a mechanical ventilator and extra oxygen for breathing.

Some of the causes of lung injury include the following :1. prematurity - the lungs, especially the air sacs, are not fully developed 2. low amounts of surfactant (a substance in the lungs that helps keep the tiny air sacs open) 3. oxygen use (high concentrations of oxygen can damage the cells of the lungs) 4. mechanical ventilation - the pressure of air from breathing machines, suctioning of the airways, use of an endotracheal tube.

Medication therapy

* Bronchodilators (to help open the airways) * Steroids to help reduce inflammation limiting fluids and giving a medication (diuretic) to help reduce excess fluid which can worsen breathing ability nutrition (to help the baby and the lungs grow) immunization against lung infection by respiratory syncytial virus (RSV) and influenza

Ventilated preterm babies who are still seriously oxygen dependent 7-10 days after birth are at serious risk of developing vhronic lung disease. Traditional regimen 250mcg/kg dexamethasone PO/IV bd for 7 days. Durand trial regimen -100mcg/kg dexamethasone PO/IV for 3 days, 50mcg/kg bd for 4 days (total 1mg/kg)

Risk factors:
1. 2. 3.

Prematurity ~ 45% in < 1750g, ~80% in <1000g RDS Increased fluid load

Patent Ductus Arteriousus

Presentation : heart murmur, hyperactive precordium, bounding pulses, hypotension, respiratory deterioration Diagnosis : Chest Xray, echocardiography Mx : Respiratory support, fluid restriction, treat anemia, diuretics, indomethacin/ibuprofen, surgery (ligation)

Intrauterine life: ductus remains open, allows blood flow from the pulmonary artery to the aorta1

At birth: declining prostagladin E2 (PGE2)1 Constriction of ductus Ductus closes within 72 hours1

PDA: ductus arteriosus is unable to close after 72 hours1 Closure of ductus arteriosus may be delayed in:2
 Premature infants  Low-birth weight infants

1. 2.

Kumar, Vinay, Nelso Fausto, and Abul Abbas. 2004. Robbins & Cotran Pathologic Basis of Disease, Seventh Edition. 7th ed. Saunders. Cotton, R B et al. 1978. Randomized trial of early closure of symptomatic patent ductus arteriosus in small preterm infants. The Journal of Pediatrics 93:647-651.

Indomethacin: NSAID, blocks cyclo-oxgenase1 Inhibits the production of prostaglandins1 Eliminates the vasodilator effect of PGE series on ductus arteriosus1 Closure of ductus arteriosus1

Indomethacin: reduces the risk of intraventricular haemorrhage2 It therefore reduces the morbidity and complications among:2
 Premature neonates between 28-30 weeks of gestational age, OR  With birth weight less than 1 kg

1. 2.

Widmaier, Eric P., Hershel Raff, and Kevin T. Strang. 2003. Vander, Sherman, Luciano's Human Physiology: The Mechanisms of Body Function. 9th ed. Mcgraw-Hill (Tx). Fowlie, P W, and P G Davis. 2003. Prophylactic indomethacin for preterm infants: a systematic review and meta-analysis. Archives of Disease in Childhood. Fetal and Neonatal Edition 88:F464-466.

Indomethacin - Prostaglandin synthetase inhibitor - Effectiveness limited to premature infants, decreases with post natal age (3-4 weeks) Prophylaxis: 0.1mg/kg Indocid IV at within 24 hours of life (after FBC platelet >50x 109/L followed by day 2 until day 3.

Indomethacin Treatment approaches: Indocid IV/PO; 0.1mg/kg daily x 6 days or 0.2mg/kg 12 hourly x 3 doses Further doses : 0.2mg/kg daily for 3 days

Indomethacin Adverse effect: 1. Reduced GFR, urine output (stop if <0.6ml/kg/d), renal impairment (urea high) 2. GIT bleeding (blood streak on feces), NEC 3. Platelet dysfunction minimal bleeding.

Indomethacin Contraindications 1. Serum creatinine >80umol/L 2. Bleeding or coagulopathy 3. Necrotizing enterocolitis (NEC) 4. Sepsis

An important cause of morbidity & mortality May occur at pre term and term Early onset (<48 hous after birth) Group B streptococcus, E. coli & staphylococcus aureus Late onset (acquired) staphylococcus epidermidis, staphylococcus aureus

Prematurity Neutropenia Maternal carrrier GBS, PROM, PPROM, fever Damaged skin Central lines Overcrowding of nurseries Inadequate hand washing

Clinical subtle (worsening of apnea, tolerance of feeds, temperature instability) or dramatic (septic shock) Lab: neutropenia, thrombocytopenia, CRP Specific : blood, urine, CSF cultures, X rays

Prevention: 1. Intrapartum antibiotic prophylaxis (GBS carrier, chorioamnionitis, maternal fever, preterm labor) 2. Hand washing 3. Breast milk 4. Prophylactic IVIG, GM-CSF/G-CSF

Treatment Antibiotic Early onset : Benzylpenicillin plus gentamycin Late onset : covers gram positive & negative organisms IVIG adjuvant Rx Supportive

Aim : To provide nutritional requirement for optimal growth & maturation of infant Why is it necessary? 1. Often need time to achieve full enteral feeds 2. Catabolism retards growth, predisposes to infections 3. Sick newborns have higher caloric requirement

1. 2. 3. 4. 5.

Premature <30 weeks and/or <1000g (1250g) >30 weeks but not likely to achieve enteral feeds by day 5 Severe IUGR Necrotizing enterocolitis (NEC) GIT anomalies

Minimal requirement to prevent catabolism at least 40kcal/kg/ay For adequate growth, 100kcal/kg/day with protein intake of 3g/kg/day for term and 3.5g/kg/day for preterm Nutritional support should be initiated within 3 days and should include protein

Through central lines preferably Peripheral lines only if <3 days, not more than 12.5% dextrose and 3.5% amino acids due to risk of thrombophlebitis Aseptic technieuq and use bacterial & particulate filter

Guaranteed caloric intake Complete absorption Does not worsen gastrointestinal problems High percentage of tolerance

Risk of infection Line sepsis, thrombophlebitis, extravasation into soft tissue- necrosis High cost Need for sophisticated infrastructure (nursing medical, technical and laboratory)

Solution A Solution B Intralipid

Carbohydrate Begin at 4-6mg/kg/min using D10-12.5% Advance by 1-3mg/kg/min to max of 12mg/kg/min Dextrose yields 3.4kcal/g Potential complication
Hyperglycemia / hypoglycemia Glycosuria and potential osmotic diuresis Cholestasis from long term high concentration infusion

Amino acids Synthetic crystaline amino acid solution (vamin), start at 1gm/kg/day; advanced by day 3-4 age to 3gm/kg/day of protein (term) and 3.7-4.0gm/kg/day (extremely LBW) Reduction in dosage may be needed in critically ill, significant hypoxaemia, suspected or proven infection and high dose steroids Adverse effect : urea and ammonia high

Intralipid Essential components Provides fatty acids and concentrated energy source for growth and development Intake of 0.25-0.5g/kg/day is required to prevent essential fatty acid deficiency yields 10kcal/g Start at 0.5g/kg/day and increase to maximum of 3g/kg/day

Do not allow lipid to exceed 60% of total caloric intake 20% solution cleared efficiently from circulation Continuous infusion over 24 hours Protect from light Complications : hyperlipidemia, increase risk of chronic lung disease, lipid overload syndrome with liver failure and coagulopathy.

Apnea of the Prematurity Osteopenia of prematurity Neonatal Seizure Neonatal Abstinence Syndrome

Definition : Cessation of respiratory for >15 to 20 seconds with a fall in heart rate to < 80/min and or oxygen saturation < 80%. Causes: hypoglycemia, fluid and electrolyte imbalance, temperature fluctuations, sepsis, anemia with or without PDA, severe brain lesion. .

Increase Afferent Input into the Respiratory Centers Cutaneous or vestibular stimulation Avoid hyperoxia Treatment of Primary Depression of Respiratory Center Treat infection Correct metabolic disturbances Administer central nervous system stimulants (aminophylline, theophylline, caffeine, doxapram)

Caffeine is recommended over aminophylline

due to it's wider margin of safety and ease of administration (once daily). Aminophylline 6mg/kg, followed by 1.53mg/kg,bd/tds after 8 to 12 hours after LD Theophylline 2.5mg/kg bd Caffeine citrate - 10mg/kg IV or PO loading dose of caffeine base (20mg/kg caffeine citrate) of 20 mg/mL solution, then 2.5 mg/kg in one daily dose.

1. Excessive diuresis 2. Increased cardiac output 3. Decreased cerebral blood flow 4. Increased blood sugar levels 5. Decreased retinal blood flow 6. Increased risk for GERD / feeding intolerance

(prominent in amino/theophyline)

DEFINITION Is a Metabolic Bone Disease of pre term infants, in which decreased bone mineral content occurs mainly as a result of lack of adequate Ca & P intake in extra uterine life.

Osteopenia of prematurity
Diagnosis: 1. Serum Phosphate: suspicious if <1.5, likely if < 1.1 mmol/L 2. Alkaline phosphatase (ALP) is above 600 or 800 IU/L are quoted (normal <360IU/L) 3. A bone x-ray will show very poor mineralisation and as the infants grow can show changes of rickets or fractures

Osteopenia of prematurity
Treatment: 1. 2. 3. Milk fortification (EBM plus with fortifier) Vitamin D about 500 IU/day is required. Pentavite provides 405 units per day. Extra phosphate supplementation - 3 mmol/kg/day in 3 divided doses, stop phosphate supplements if the serum phosphate is >1.8 mmol/L

The incidence of seizures in infants born at term is 1 3 per 1000 live births; the incidence is even higher in preterm infants, ranging from 1 13% of very low birth weight infants. Seizures are the most frequent manifestation of neonatal neurological diseases. It is important to recognize seizures, determine their etiology and treat them because: 1. The seizures may be related to significant diseases and may require specific treatment 2. The seizures may interfere with supportive measures e.g. feeding and assisted respiration for associated disorders 3. The seizures per se may be a cause of brain injury.

Immature brain relative excess of excitatory neurotransmitters and receptors. Neonatal seizures are usually focal, often short lasting.

Manifestations include: 1. Ocular phenomena (staring, blinking, eye deviation, eye opening) 2. Oral phenomena (mouthing, chewing, sucking, smiling) 3. Autonomic phenomena (change in blood pressure and/or heart rate, pallor, increased salivation or secretions; central apnoea occurring rarely as the only seizure manifestation) 4. Fragmentary body movements (limb posturing, swimming, pedalling).

A constellation of signs and symptoms which result from the abrupt cessation of a drug to which the fetus/neonate has become physiologically dependent

Opiates

NonNon-opiates

Heroin Methadone Morphine Other

 Oxycodone

Alcohol Barbiturates Benzodiazepines SSRIs Other (caffeine, tricyclics, valproate, antihistamines)

Heroin addiction on the rise

 0.1% pregnant women  Less expensive, purer, & more potent, even via

oral route

Prescription drugs
 Available via the internet

Eases symptoms of physical dependency Blocks euphoria Longer duration than heroin (T/2=24-36 hrs) Increases fetal safety
 Enables mother to attend to her health & nutrition  Stabilizes maternal metabolic processes/ ANS  Prevents fetal withdrawal

Optimal fetal growth

Accelerated clearance from maternal circulation in late pregnancy due to

 Larger blood volume  Increased metabolism (progestins) (progestins)  Higher fetal tissue concentration

Pregnant women may need an increased/ split dose.

CNS = majority of signs especially Irritability & sleep disturbance

In preterms less frequent & milder Non specific R/O other conditions sepsis, hypoglycemia, hyperthyroidism, hypocalcemia, hypomagnesemia, asphyxia

W I T H

- wakefulness - irritability -tremors, twitching, tachypnea - hyperventilation, hypertonia, hyperpyrexia, hypertonia, hyperaccusis, hyperaccusis, hiccups D - diarrhea, diaphoresis, R - rub marks A - alkalosis W - weight loss A - apnea L - lacrimation, lacrimation, S - seizures (myoclonic), sneezing, skin (myoclonic), mottling

Disturbed sleep 53% Mottling 53% Excess sucking 45% Tremors 43% Tachypnea 43% Hypertonia 41% Fever 40% Seizures 2-11% (often later)

Paregoric 0.2-0.5 ml/dose q 3-4 p.o. or 4-6 drops q 4-6h; may increase by 2 drops until clinical improvement Improves most of the withdrawal symptoms especially diarrhea, taper dose by 10-20% per day over 2-4 week after symptoms stable for 3-5 days. Neonatal Opium Dilution 0.4% solution (contains 0.4 mg morphine equivalent per ml) guidelines: 0.8 ml/kg/day for NAS 8-10 1.2 ml/kg/day for NAS 11-13 1.6 ml/kg/day for NAS 14-16 2.0 ml/kg/day for NAS >16 Doses given orally every 3-4 h with feeds ( not prn)

Phenobarbital 15-20 mg/kg/day loading dose to achieve level of 2040 mg/ml. Maintenance dose =2-8 mg/kg/day. Taper dose by 10-20% per day after symptoms stable for 3-5 days. Diazepam 0.3-0.5 mg/kg q 8 h; initial dose i.m then p.o Allows rapid suppression of symptoms, decreased suck, avoid in jaundice or premature infants.

Methadone 0.1-0.5 mg/kg/day divided q 4 to 12 h Increase by 0.05mg/kg/dose until symptoms are well controlled Taper dose by 10-20% per day over 1 mo Treatment usually longer (5 days-4 mo) Long half-life (26 h )

Chlorpromazine 0.5-0.7 mg/kg/dose loading then 2-2.8 mg/kg/day in divided doses q 6 h Decrease dose over 2-3 wk Clonidine 0.5-1 ug/kg single dose then 3-5 ug/kg/day divided dose q 4-6 h Increase by 0.5 ug/kg over 1-2 days until maintenance dose is achieved

Exaggerated crying curve in first 2 to 3 months By 4 months: most infants have no s/ s of withdrawal Severity of NAS does not affect prognosis.

The End