Neonates

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Chapter 9 Neonates

M.P. Ward Platt

• The survival of very premature babies has been greatly increased through the use of antenatal betamethasone and neonatal surfactant treatment to prevent and treat surfactant deficiency.

• The feto-placental unit creates a unique route for drug delivery.

• Drug disposition and metabolism in the neonate are very different from those at any other time of life.

• Preterm babies grow very fast, so doses have to be re-calculated at regular intervals.

• Drug elimination in the neonate can be much slower than in children, especially in the first week, so dose intervals have to be longer.

The earliest in pregnancy at which newborn babies can sometimes survive is around 23 weeks’ gestation, when survival is about 10% for liveborn babies. Conventionally, any baby born at less than 32 weeks is regarded as being at relatively high risk of death or disability. About 7.5% of all births are technically ‘premature’ (<37 weeks) but only 1.4% of births take place before 32 weeks of gestation. Likewise, 7% of all babies are low birth weight (LBW), for example, <2500 g, and 1.4% are very low birth weight (VLBW). However, it is the gestation at birth rather than the birth weight which is of more practical and prognostic value. The definitions of selected terms used for babies are given in Table 9.1.

Table 9.1 Definitions of terms

Normal length of human pregnancy (term)	37 up to 42 completed weeks of gestation
Preterm	<37 weeks of gestation at birth
Post-term	42 completed weeks onwards
Neonatal period	Up to the 28th postnatal day
Low birth weight (LBW)	<2500 g
Very low birth weight (VLBW)	<1500 g
Extremely low birth weight (ELBW)	<1000 g

Because mothers with high-risk pregnancies will often be transferred for delivery to a hospital capable of providing neonatal intensive care, the proportion of preterm and LBW babies cared for in such units is greater than in smaller maternity units in peripheral hospitals. In the population as a whole, between 1% and 2% of all babies will receive intensive care, and the most common reason for this among preterm babies is the need for respiratory support of some kind. Over three-quarters of babies born at 25 weeks’ gestation now survive to discharge home.

Babies of less than 32 weeks’ gestation invariably need some degree of special or intensive care, and generally go home when they are feeding adequately, somewhere between 35 and 40 weeks of postmenstrual age. So although in epidemiological terms the neonatal period is up to the first 28 postnatal days, babies may be ‘neonatal’ inpatients for as long as 3 or 4 months; during this time their weight may triple and their physiology and metabolism will change dramatically.

Drug disposition

Absorption

An important and unique source of drug absorption, available until birth, is the placenta. Maternal drugs pass to the fetus and back again during pregnancy, but from delivery, any drugs present in the neonatal circulation can no longer be eliminated by that route and must be dealt with by the baby’s own systems. Important examples of maternal drugs which may adversely affect the newborn baby include opiates given for pain relief during labour, β-blockers given for pregnancy-induced hypertension and benzodiazepines for eclamptic seizures. In addition, a mother may be given a drug with the intention of treating not her but her fetus. An example of this is the use of corticosteroids to promote fetal lung maturation when preterm delivery is planned or expected. In this situation, betamethasone is normally the drug of choice as prednisolone is metabolised in the placenta and does not reach the fetus.

Enteral drug absorption is erratic in any newborn baby and unavailable in the ill baby because the stomach does not always empty effectively. Therefore, most drugs are given intravenously to ensure maximum bioavailability. Some drugs, such as paraldehyde and diazepam (for neonatal seizures) and paracetamol (for simple analgesia), can be given rectally. The trachea may be used as the preferred route of administration when surfactant administration is required or where adrenaline (epinephrine) is given for resuscitation. The buccal route may be used to administer glucose gel in the treatment of hypoglycaemia. In the very preterm baby of 28 weeks’ gestation or less, the skin is extremely thin and a poor barrier to water loss; consequently it is also permeable to substances in contact with it. This is harmful to the baby if there is prolonged skin contact with alcohol, as in chlorhexidine in 70% methylated spirit, which causes severe chemical burn and has resulted in systemic methyl alcohol poisoning. The intramuscular route is normally avoided in premature babies because of their small muscle bulk, although the notable exceptions to this are the administration of vitamin K and naloxone.

Distribution

Drugs are distributed within a baby’s body as a function of their lipid and aqueous solubility, as at any other time of life. The main difference in the neonate is that the size of the body water pool under renal control is related not to the baby’s surface area but to body weight. Furthermore, the absolute glomerular filtration rate increases logarithmically with postconceptional age irrespective of the length of a baby’s gestation. This has implications for predicting the behaviour of water-soluble drugs such as gentamicin. The amount of adipose tissue can vary substantially between different babies. Any baby born more than 10 weeks early, and babies of any gestation who have suffered intrauterine growth restriction, may have little body fat. Conversely, the infant of a diabetic mother may have a particularly large fat layer and this affects the retention of predominantly lipid-soluble drugs. Protein binding in the plasma is influenced by the amount of albumin available and this in turn is related to gestation, with albumin values found 12 weeks prior to term being only two-thirds of adult concentrations.

Metabolism

The metabolic fate of drugs in the newborn is not qualitatively different to that in the older child, for example, hydroxylation, oxidation and conjugation to sulphate or glucuronide. It is the efficiency with which these processes are carried out that distinguishes the baby from the older person. In addition to the immaturity of the metabolic pathways for drug disposal, drug metabolism is also affected by the physiological hyperbilirubinaemia of the newborn. The bilirubin can compete both for enzyme-binding sites and for glucuronate, and may thus affect drug metabolism for as long as unconjugated hyperbilirubinaemia persists.

Elimination

The relative immaturity of hepatic and renal function results in correspondingly slow elimination of most drugs from the neonate. This is not necessarily a problem, so long as due account is taken of the slow elimination and dose intervals are modified accordingly. It may even be a useful property, as with phenobarbital, which when given as a loading dose (usually 20 mg/kg) will remain in circulation for days in useful therapeutic quantities, often avoiding the need for further doses. On the other hand, drugs such as gentamicin and vancomycin, which have a relatively narrow therapeutic index, must be given far less frequently than in children or adults and serum drug levels must be assayed to avoid toxicity.

There has been little study of pharmacodynamics in the term or preterm neonate. Most clinicians work on the assumption that the kinetics of drug behaviour are so different in this group of patients that the pharmacodynamic properties must follow the same pattern. In practice, the most important pharmacodynamic effect is probably that of the behaviour of opiates derived from the mother in labour. Pethidine and diamorphine are the opiates most likely to cause significant respiratory depression in the neonate. Such respiratory depression can be treated with naloxone, and a special neonatal preparation (20 µcg/mL) is available. However, after birth the opiates and their metabolites have a long serum half-life in the baby whereas the naloxone is rapidly eliminated. The initial dramatic effect of naloxone can give a false sense of security, as the baby may become narcosed after a few hours following transfer to the postnatal ward. To try to prevent this late-onset narcosis, adult naloxone (400 µcg/mL) may be given intramuscularly to ensure it remains active over several hours. Even when the respiratory effects have disappeared, opiates may have prolonged behavioural effects on both mother and baby.

Major clinical disorders

Respiratory distress syndrome (RDS)

Among preterm babies the most commonly encountered disorder is RDS (also sometimes called hyaline membrane disease from its appearance on lung histology, or surfactant deficiency lung disease in recognition of the aetiology). The root cause of this disease is the lack of sufficient pulmonary surfactant at the time of birth. The condition is rare in babies born at or near term and becomes increasingly likely the more preterm a birth takes place. It is now quite unusual to see classical RDS because it is prevented both by the use of antenatal betamethasone in the mother and the postnatal administration of surfactant to babies at highest risk (see below).

Clinically, RDS is manifested by obvious difficulty with breathing, with nasal flaring, rib recession, tachypnoea and a requirement for oxygen therapy. The natural history is that RDS becomes worse over the first 2 days, reaches a plateau and then gradually improves. The use of antenatal steroid therapy to the mother, and surfactant therapy for the infant, has not only transformed the clinical course of this condition but also greatly reduced mortality.

A relatively big baby born around 32–34 weeks of gestation with mild RDS may need no more treatment than extra oxygen. In contrast, smaller, more premature or more severely affected babies need some degree of mechanical assistance: either continuous positive airway pressure by nasal prongs or full artificial ventilation through an endotracheal tube. A few babies require high inspired concentrations of oxygen (up to 100%) for several days. Fortunately, pulmonary oxygen toxicity is not as much a problem to the neonate as it is to the adult, though it may have a causal role in the development of bronchopulmonary dysplasia. The major concern is the damage that prolonged arterial hyperoxia can do to the retina, resulting in retinopathy of prematurity. The goal is to give enough inspired oxygen to keep the arterial partial pressure within a range of about 6–12 kPa.

Mechanical ventilation is not a comfortable experience, for adults or children, but it has taken a long time to appreciate that this may also be true for premature babies. Paralysing agents such as pancuronium are sometimes given to ventilated neonates but these only prevent the baby from moving and are not sedative. Pancuronium is widely used, partly because it wears off slowly so that the baby is not suddenly destabilised. Shorter acting agents such as atracurium are often used for temporary paralysis for intubation. Whether or not the baby is paralysed, morphine is commonly given either as intermittent doses or as an infusion, to provide narcosis and analgesia to reduce the distress of neonatal intensive care.

Antenatal steroids given to the mother reduce the incidence, severity and mortality of RDS caused by surfactant deficiency. Unfortunately, it is not possible to identify and treat all mothers whose babies could benefit. Babies of less than 32 weeks’ gestation gain most benefit because they are at greatest risk of death and disability from RDS. Optimum treatment is four oral doses of 6 mg betamethasone, each given 12-hourly, or two doses of 12 mg intramuscularly 24 h apart.

Similarly, the introduction of exogenous surfactant, derived from the pig or calf, has revolutionised the management of RDS. Natural surfactants derived from animals are currently more effective than artificial synthetic ones. The first dose should be given as soon as possible after birth since the earlier it is given, the greater the benefit (Soll, 1999).

There are several other important ways of treating babies in respiratory failure. Inhaled nitric oxide dilates pulmonary arterioles and lowers the excessive pulmonary blood pressure which often complicates respiratory failure. Persistent pulmonary hypertension may also complicate early onset septicaemia and meconium aspiration syndrome; in term and near-term babies, nitric oxide is both more effective than the previous drug therapies and much less likely to lead to systemic hypotension. However, it does not reduce mortality or major complications when used in babies with birth weights less than 1500 g (Van Meurs et al., 2005).

For some babies of at least 34 weeks of gestation and at least 2 kg birth weight, extracorporeal membrane oxygenation (ECMO), in which a baby is in effect put on partial heart–lung bypass for a few days, may be life-saving when ventilation and nitric oxide fails (ECMO Collaborative Trial Group., 1996).

Patent ductus arteriosus (PDA)

PDA can be a problem in the recovery phase of RDS, and usually shows itself as a secondary increase in respiratory distress and/or ventilatory requirement, an increasing oxygen requirement, wide pulse pressure and a characteristic heart murmur. Physiologically, as pressure in the pulmonary artery falls, an open duct allows blood from the aorta to flow into the pulmonary artery, which engorges the lungs and reduces their compliance, while putting strain on the heart. Echocardiography is used to confirm the clinical suspicion. About one-third of all babies with birth weights less than 1000 g will develop signs of PDA, for example, the characteristic heart murmur, but treatment is only needed when the baby is haemodynamically compromised. When treatment is needed the options are either medical treatment (with indometacin or ibuprofen) or surgical ligation.

Indometacin is usually given intravenously in the UK, because when given enterally its absorption is unpredictable and it may need to be given before the baby has started enteral feeds. The alternative is intravenous ibuprofen. Potential serious side effects of both drugs include renal impairment, gastric haemorrhage and gut perforation. Surgery is considered when one or more courses of medical treatment fail to close the PDA or if drugs are contraindicated for any reason. There are no good randomised controlled trials to guide clinicians on the best approach to managing PDA.

Bronchopulmonary dysplasia (BPD)

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