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Drugs used in prematurity
Current Obstetrics & Gynaecology (2000) 10, 162–167 © 2000 Harcourt Publishers. Ltd doi:10.1054/cuog.2000.0112, available online at http://www.idealibrary.com on
Drugs
Drugs used in prematurity
J. McIntyre and S. Conroy
neonatal intensive care. Surfactant replacement reduces the risk of a baby with RDS dying by 40% and the risk of pneumothorax by 30–70%.1, 2 Combining postnatal surfactant and antenatal steroids is more effective than either treatment alone.3 The giving or withholding of surfactant based on arbitrary gestational or weight limits is not supported by the data available, with even the smallest of babies showing some benefit.4, 5 Since surfactant undoubtedly improves the outlook for ventilated babies the focus of debate has shifted to what product (natural vs synthetic) and when to give it (prophylaxis vs rescue).
INTRODUCTION The aim of this article is to introduce the reader to some important and common drugs used in neonatal intensive care units (NICUs). Drugs are an integral part of intensive care and impact on many aspects of managing the sick newborn. However, selecting which drug to use, when to use it, at what dose and for how long is far from straightforward. The choice is bewildering; there are large variations in size of infants and drug handling capacity, and for an individual there will be marked changes in these parameters during a stay on NICU. By focusing on some key areas we hope to give insight into current practice and the therapeutic dilemmas in using drugs in the newborn. The following topics will be considered: • • • • • •
Natural versus synthetic There are four licensed surfactants for use in the UK, two synthetic and two derived from animal sources (see Table 1). Animal-derived surfactants have a more rapid onset of action. Studies comparing natural and synthetic surfactants have usually involved Survanta and Exosurf. Meta-analyses of suitable studies suggest a reduced pneumothorax rate and a trend towards reduced mortality in the natural group.6 However, it would take large comparative trials to resolve which is better.2
Surfactant Antibiotics Steroids Anticonvulsants Analgesics Indomethacin.
SURFACTANT Surfactant is a complex mixture of phospholipids, neutral lipids and specific proteins. It is synthesized and stored in alveolar type II cells. It reduces surface tension in the alveoli so easing expansion and reducing the tendency to atelectasis. Exogenous surfactant to treat neonatal respiratory distress syndrome (RDS) has been a major advance in
Prophylaxis versus rescue Randomized controlled trials show surfactant treatment given once a preterm baby is intubated (prophylaxis) is more effective than treatment a few hours later (rescue).7 Prophylaxis reduced mortality with an odds ratio (and 95% confidence intervals) of 0.55 (0.41–0.73). There were similar improvements in incidence of air leak syndromes. Overall, prophylactic treatment would save about seven more lives than rescue treatment for every 100 babies treated.
J. McIntyre, Senior Lecturer in Child Health, S. Conroy, Lecturer in Paediatric Clinical Pharmacy, Derbyshire Children’s Hospital, University of Nottingham, Derby, UK.
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Table 1 Surfactants licensed for use in the UK Name
Source
Dose
Volume
Cost
Poractant alfa (Curosurf)
Porcine
1.2 ml/kg
£400.00 for 1.5 ml vial
Beractant (Survanta)
Bovine
4 ml/kg
£306.43 for 8 ml vial
Pumactant (ALEC)
Synthetic
1.2 ml
£150.00 per vial
Colfosceril (Exosurf)
Synthetic
100 mg/kg+ two further doses at 12 and 24 h if necessary 100 mg/kg up to maximum of four doses in 48 h 100 mg repeated at 1 and 24 h 67.5 mg/kg repeated at 12 and 24 h
5 ml/kg
£306.43 for 8 ml vial
Other indications Other conditions occurring in the neonatal period can result in a secondary deficiency of surfactant. Exogenous surfactant may therefore have a role in conditions such as meconium aspiration syndrome, pneumonia, pulmonary haemorrhage or where pulmonary hypoplasia is a complicating factor e.g. in congenital diaphragmatic hernia.
Prompt treatment of sepsis is essential to avoid rapid deterioration. Most units in the UK use a combination of a broad-spectrum penicillin or cephalosporin with an aminoglycoside antibiotic e.g. benzylpenicillin and gentamicin as first line therapy for likely or suspected infection. These will usually be given for 48 h until culture results are known, then stopped if cultures are negative. With positive cultures, antibiotic choice can be adjusted in light of sensitivity results.
ANTIBIOTICS Bacterial infections are a major cause of morbidity and mortality in NICU. The incidence of neonatal sepsis ranges from 1 to 10 per 1000 live births worldwide. Despite advances in antibiotic therapy, mortality remains high at 20–30%.8 The major pathogens in the first few days of life are usually maternally transmitted and include Group B Streptococcus, Escherichia coli, enterococci and Listeria monocytogenes. Haemophilus influenzae is also important in preterm babies. Prophylactic antibiotics to cover these organisms are used for babies with risk factors for infection such as: • maternal membranes ruptured more than 24 h predelivery; • unexplained maternal pyrexia; • known recent Group B Strep. cultured in HVS; • umbilical catheterization more than 24 h after birth; • suspected Listeria infection in ill baby with stained liquor; • babies showing rapid unexplained deterioration. Nosocomial late onset infections occur in up to 60% of infants in NICU.9 Coagulase-negative staphylococci e.g. Staph. epidermidis are important pathogens where umbilical and central catheters are in situ. Pseudomonas, Klebsiella and Serratia spp. are other potential infecting organisms. Very low birth weight babies are particularly susceptible to nosocomial infections resulting in septicaemia, meningitis and pneumonia, with approximately 18% of babies under 1500 g being affected.10
Penicillins Benzylpenicillin is active against most streptococci (including Group B Strep.). It is eliminated mainly by the kidney. Since renal function is immature in the neonate, particularly the preterm neonate, doses are adapted to compensate for reduced excretion, and subsequently adjusted with increasing postnatal age and renal function. Ampicillin is preferred in some centres and is the drug of choice if Listeria infection is likely. Flucloxacillin and an aminoglycoside are a combination used by many centres for initial treatment of late onset infection. Aminoglycosides Gentamicin, netilmicin or tobramycin may be used. These are primarily active against aerobic Gramnegative bacilli. Glomerular filtration is the major route of excretion. As with all renally excreted drugs, doses must be adjusted to compensate for the immaturity of the neonatal kidney. These drugs are highly water soluble, with a large volume of distribution in the newborn. Therapeutic drug monitoring (TDM) is necessary to ensure effective, non-toxic serum concentrations. Renal function increases with gestational age, postnatal age, weight and the use of antenatal steroids. It is decreased by the pre- or postnatal use of indomethacin, perinatal asphyxia and the presence of a persistent ductus arteriosus. Protocols for aminoglycoside dosing attempt to account for these variables. Work is ongoing to establish ideal dose schedules for safe and effective therapy. Achieving therapeutic peak
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serum concentration in the first 24 h of therapy is associated with improved outcomes in adults. The importance of this in neonates is not clear, but loading doses or high doses given at extended dose intervals to compensate for the large volume of distribution and reduced capacity for excretion may be the way forward. Nephrotoxicity and ototoxicity are major sideeffects in adult patients. Nephrotoxicity seems to be less common in the neonate, but controversy remains regarding the incidence of ototoxicity since this can be compounded by many other factors such as prematurity itself, meningitis and intracranial haemorrhage. Cephalosporins Third generation cephalosporins including cefotaxime and ceftazidime are active against the major neonatal pathogens including Group B Strep. and Gramnegative bacilli such as E. coli. They are widely used in the treatment of neonatal meningitis. Cefotaxime is rapidly metabolized by esterase action in the liver, erythrocytes and other tissues. Its half-life is inversely related to gestational and postnatal age. Ceftazidime is eliminated primarily renally in unchanged form. Due to the reduced nephrotoxicity of cephalosporins compared to aminoglycosides some units use a combination of a penicillin and a cephalosporin. This avoids the need for blood sampling for TDM. Glycopeptides Vancomycin is a glycopeptide antibiotic active against Gram-positive bacteria including multidrugresistant strains. The recent increase in infections due to methicillin-resistant coagulase-negative Staph. aureus (MRSA) has resulted in an important role for vancomycin in NICU.11 It is renally eliminated unchanged. Dosage recommendations vary but are based on factors highlighted above. TDM is generally recommended but there is debate regarding the need for this.11 It is nephrotoxic but rarely ototoxic in the neonate. Concomitant administration with aminoglycosides significantly increase nephrotoxicity. Teicoplanin is better tolerated, its longer half-life allows it to be given less frequently and TDM is unnecessary. Metronidazole Metronidazole is active against anaerobic bacteria and is frequently used to treat necrotizing enterocolitis (NEC). Doses of all these drugs vary in different NICUs due to lack of clear evidence. The introduction of Medicines for Children12 may go some way towards standardization in the UK.
DEXAMETHASONE Chronic lung disease (CLD) or bronchopulmonary dysplasia (BPD) is characterized by the need for prolonged mechanical ventilation or oxygen accompanied by specific chest X-ray changes. It develops in 30–40% of infants <1500 g ventilated for RDS and is a significant cause of morbidity. Various strategies and drug treatments have been tried to reduce the incidence and severity of CLD. Dexamethasone has been widely used in a prophylactic role and for therapy in established CLD. The improvement in respiratory status seen after dexamethasone may involve a number of mechanisms such as a reduction in pulmonary oedema, increased surfactant production, enhanced adrenergic activity and inhibition of prostaglandin and leucotrine synthesis. In the Collaborative Dexamethasone Trial it was used to treat infants with established CLD at around 3 weeks of age.13 Active treatment significantly reduced the duration of further assisted ventilation (median days for survivors 11 vs 17.5) but there was no difference in total time of oxygen dependence or length of hospital stay. Facilitation of early extubation attracts many to use dexamethasone earlier in the course of CLD. However, initiating treatment at 2 weeks compared with starting at 4 weeks was found to be more hazardous and no more beneficial.14 A systematic review of late postnatal corticosteroids for CLD showed no effect on mortality or most other outcomes and concluded that the benefits of late corticosteroid therapy may not outweigh the actual or potential adverse outcomes.15 Early dexamethasone to prevent CLD has also attracted much interest. Dexamethasone may help limit the early inflammatory responses seen in the lungs of ventilated infants, a process thought to contribute to CLD. A 12-day course of dexamethasone in ventilated infants <1600 g and started within 36 h of birth did not decrease the incidence of CLD and/or death; however, it did appear to reduce oxygen dependency at 36 weeks after conception.16 A recent systematic review and meta-analysis of early postnatal dexamethasone for prevention of chronic lung disease found that dexamethasone started between 7 and 14 days of age reduced mortality and chronic lung disease.17 Despite widespread use and short-term benefits in lung function there are significant side-effects, such as hyperglycaemia, bacteraemia, hypertension and impaired growth.14, 15, 17 Infants may also be at risk of other potential adverse effects such as gastrointestinal perforation, severe retinopathy of prematurity, necrotizing enterocolitis and intraventricular haemorrhage, although studies to date have not confirmed a significant increase in these events. A particular area of concern that awaits more data is that early dexamethasone may have adverse effects on neurodevelopmental outcome.
Drugs used in prematurity ANTICONVULSANTS The incidence of neonatal seizures is about 2.6 per 1000 live births, with increased rates in preterm infants.18 Management of seizures requires identifying and treating the underlying condition (e.g. infection, intracranial bleeds, metabolic disorders, hypoxia ischaemia, developmental defects and drug withdrawal) and control of the seizures. Seizures have a number of harmful effects (e.g. increased cerebral metabolism, hypoxia, hypercarbia and hypertension) and quick effective control is essential to minimize further cerebral injury. Drug treatment takes place alongside general supportive measures to ensure adequate ventilation and perfusion. The usual sequence of therapy is phenobarbitone, phenytoin and benzodiazepines.19 Phenobarbitone For acute treatment the properties of phenobarbitone can be helpful: it enters CSF rapidly and efficiently; the blood level is predictable from the dose given; intravenous, intramuscular and oral routes are available.19 A loading dose of phenobarbitone at 20 mg/kg with additional doses up to a total of 40 mg/kg can achieve seizure control in up to 70% of infants.20 Phenobarbitone is also used for maintenance therapy. Because of its long half-life, once-daily dosing can be adequate. However, its liver enzyme inducing properties mean a dose increment may be required a few weeks after starting treatment. Phenytoin Phenytoin (20 mg/kg intravenously) is often used acutely if seizures persist after loading with phenobarbitone. It has to be given slowly to avoid cardiac arrhythmias and is an irritant to veins. However, maintenance therapy is difficult because of its zero order kinetics, whereby a small increase in dose can result in large increases in blood concentrations due to saturation of the enzyme responsible for its metabolism. Careful monitoring and attention to blood levels is essential. Benzodiazepines Benzodiazepines are effective anticonvulsants. In the newborn they are used as second or third line treatments for acute seizures. Lorazepam has potential advantages over diazepam in that it has an equally rapid onset of action (usually 2–3 min) but is not so rapidly redistributed from the brain giving a longer duration of action. Clonazepam may be equally effective. ANALGESICS Neonates, both preterm and term, feel pain. In the NICU there are numerous painful procedures such
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as venous and arterial cannulation, heel pricks, intubation, lumbar puncture and chest drain insertion. Disease states such as necrotizing enterocolitis are also painful. Surgical procedures require adequate intra- and post-operative analgesia. Repeated painful events in the NICU can have detrimental effects on the newborn’s clinical state and may contribute to complications such as intraventricular haemorrhage or periventricular leukomalacia.21 Despite this recognition a neonate is less likely to receive analgesia for a painful procedure than an older child.22 Pain assessment Assessing neonatal pain uses a variety of methods such as measurement of physiological parameters (e.g. increases in heart rate, respiratory rate, blood pressure, palmar sweating), stress hormones (e.g. changes in adrenaline, noradrenaline, cortisol concentrations) and behavioural changes (e.g. facial expression, body movements and cry). It is essential that a valid pain assessment tool be used to monitor the efficacy of analgesia administered and to aid development of appropriate analgesic protocols.23 Topical anaesthesia The two most commonly used topical anaesthetics in children are EMLA cream (Astra) and Ametop (Smith and Nephew). They are not licensed for use in neonates although interest is growing in this area. Fears of methaemaglobinaemia in the neonate caused by the prilocaine component of EMLA are now thought to be unfounded.24 Morphine For relief of severe pain and to facilitate ventilation, morphine is the opiate with which there is most experience in neonatal patients and the most in-depth understanding of the pharmacokinetics of the drug. A loading dose is necessary to obtain appropriate initial serum concentrations followed by continuous intravenous infusion. Respiratory depression, urinary retention and constipation may occur and patients must be closely monitored. However, neonates should not be deprived of the benefits of this drug due to fears of side-effects. Paracetamol Although neonates metabolize paracetamol by a different route compared to older children and adults, mainly by sulphation rather than glucuronidation, it has been shown to be safe and can be used when a mild analgesic or anti-pyretic is required.
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Other measures Several studies have documented the analgesic effects of concentrated sucrose and glucose solutions in newborn babies undergoing minor procedures. It has been suggested that a pacifier in conjunction with these solutions may have a synergistic analgesic effect.25 This may however be frowned upon in units with a strong breast-feeding policy.
INDOMETHACIN Shortly after birth, physiological processes usually effect prompt functional closure of the ductus arteriosus. Precise mechanisms are incompletely understood but it is known that constriction of the ductus arteriosus can be inhibited by prostaglandin E and promoted by inhibiting prostaglandin synthesis. The focus of this discussion is the preterm infant where persistent ductus arteriosus (PDA) has different management implications from PDA in term infants. The incidence of PDA in preterm babies with RDS is about 40% on day 3 of life.26 The undesirable consequences of left to right shunting of blood through a PDA include increased pulmonary blood flow, increased cardiac workload and reduced renal and gastrointestinal blood flow. There is also increased risk of intraventricular haemorrhage and chronic lung disease. Indomethacin, a prostaglandin synthetase inhibitor, has been used for pharmacological closure of a PDA for over 20 years. Success in achieving initial closure is about 80–90% but after stopping treatment relapse rate may be around 20–40%.27–29 However, there are potential complications such as altered platelet and renal function and decreased cerebral, mesenteric and renal blood flow. Various regimes have been evaluated e.g. short course (1–2 days) versus long course (6–7 days) and early prophylaxis versus late symptomatic.30, 31 A prolonged low dose of indomethacin (0.1 mg/kg daily for 6 days) resulted in a greater initial closure rate of PDA, lower reopening rate and fewer infants experiencing a rise in serum creatinine or urea compared with a short course (0.2 mg/kg 12 hourly for three doses).28 However, more recent studies have found no advantage of prolonged low dose regimes compared with short courses.29 The role of prophylactic indomethacin has also been addressed.30 For small babies <1750 g, indomethacin within 24 h had some short-term benefits: a lower incidence of symptomatic PDA and a reduction in grade 3/4 intraventricular haemorrhage. Although there appeared to be a trend to overall reduced mortality in treated infants, respiratory outcomes were similar and there was also a trend to increased incidence of necrotizing enterocolitis. The effect on long-term neurological outcome is not known. Clearer understanding of long-term outcomes and adverse effects is required before routine prophylactic indomethacin becomes established.
The clinical benefits of pharmacological closure of the PDA and the wish to reduce side-effects has led to the evaluation of other agents. Of particular interest is ibuprofen which seems to be as effective as indomethacin but with fewer renal side-effects.32
SUMMARY Drug selection is just one of the many challenges in caring for the newborn infant, especially the extremely small premature baby delivered at the edges of viability. Specific conditions are occurring at a time of unique physiological adaptations. Knowledge of these processes needs to be combined with understanding of basic pharmacological principles if drugs are to be used safely and effectively. Continuing questioning and evaluation of our therapeutic interventions is required to ensure the best practice is established. REFERENCES 1. Halliday H. Surfactant therapy in neonates. Paed Perinatal Drug Therapy 1997;1:30–40. 2. Sweet D, Halliday H. Surfactant therapy. Curr paediatrics 1998;8:103–107. 3. Jobe A, Mitchell B, Gunkel J. Beneficial effects of the combined use of prenatal corticosteroids and postnatal surfactant on preterm infants. Am J Obstet Gynecol 1993;168:508–513. 4. American Exosurf Neonatal Study Group. Controlled trials of a single dose of synthetic surfactant at birth in premature infants weighing 500–699 grams. J Pediatr 1992;120:S3–S12. 5. Ten Centre Study Group. Ten centre trial of artificial surfactant (artificial lung expanding compound) in very premature infants. BMJ 1987;294:991–996. 6. Soll R. Natural surfactant extract vs synthetic surfactant in the treatment of established respiratory distress syndrome (Cochrane review). Update Software, 4th edn, 1998. 7. Morley C. Systematic review of prophylactic vs rescue surfactant. Arch Dis Child 1997;77:F70–F74. 8. Fanos V, Dall’ Agnola A. Antibiotics in neonatal infections: a review. Drugs 1999;58:405–427. 9. Fowlie P, Gould C, Parry G, Phillips G, Tarnow-Mordi W. CRIB (clinical risk index for babies) in relation to nosocomial bacteraemia in very low birthweight or preterm infants. Arch Dis Child 1996:F49–F52. 10. Van den Anker J. Antibiotics in neonates. Paed Perinatal Drug Therapy 1997;1:41–45. 11. Grimsley C, Thomson A. Pharmokinetics and dose requirements of vancomycin in neonates. Arch Dis Child 1999;F221–F227. 12. Medicines for Children. London: Royal College of Paediatrics and Child Health, 1999. 13. Collaborative Dexamethasone Trial Group. Dexamethasone therapy in neonatal chronic lung disease: an international placebo-controlled trial. Pediatrics 1991;88:421–427. 14. Papile LA, Tyson JE, Stoll BJ, et al. A multicenter trial of two dexamethasone regimens in ventilator-dependent premature infants. N Engl J Med 1998;338:1112–1118. 15. Halliday H, Ehrenkranz R. Delayed (>3 weeks) postnatal corticosteroids for chronic lung disease in preterm infants. The Cochrane Library 1999;3. 16. Tapia JL, Ramirez R, Cifuentes J, et al. The effect of early dexamethasone administration on bronchopulmonary dysplasia in preterm infants with respiratory distress syndrome. J Pediatr 1998;132:48–52. 17. Bhuta T, Ohlsson A. Systematic review and meta-analysis of early postnatal dexamethasone for prevention of chronic lung disease. Arch Dis Child 1998;79:F26–F33.
Drugs used in prematurity 18. Ronen G, Penney S, Andrews W. The epidemiology of clinical neonatal seizures in Newfoundland: a population-based study. J Pediatr 1999;134:71075. 19. Volpe J. Neonatal seizures. In: Neurology of the newborn. 3rd edn. London: W.B. Saunders, 1995:172–207. 20. Gilman J, Gal P, Duchowny M, Weaver R, Ransom J. Rapid sequential phenobarbital treatment of neonatal seizures. Pediatrics 1989;83:674–678. 21. Anand K, McIntosh N, Lagercrantz H et al. Analgesia and sedation in preterm neonates who require ventilatory support: results from the NOPAIN trial. Neonatal outcome and prolonged analgesia in neonates. Arch Ped Adol Med 1999;153:331–338. 22. Bauchner H, May A, Coates E. Use of analgesic agents for invasive medical procedures in pediatric and neonatal intensive care units. J Pediatr 1992;121:647–649. 23. Choonara I. Pain in neonates, assessment and management. Semin Neonatol 1998;3:137–142. 24. Rutter N. Topical local anaesthesia in the newborn. Paed Perinatal Drug Therapy 1997;1:20–24. 25. Carbajal R, Chauvet X, Chouderc S, Olivier-Martin M. Randomised trial of analgesic effects of sucrose, glucose and pacifiers in term neonates. BMJ 1999;319:1393–1396.
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26. Ellison R, Peckham G, Lang P, Talner N, Lerer T, Lin L. Evaluation of the pretem infant for patent ductus arteriosus. Pediatrics 1983;71:364–372. 27. Couser R, Ferrara B, Wright G, et al. Prophylactic indomethacin therapy in the first twenty-four hours of life for the prevention of patent ductus arteriosus in preterm infants treated prophylactically with surfactant in the delivery room. J Pediatr 1996;128:631–637. 28. Rennie J, Cooke R. Prolonged low dose indomethacin for persistent ductus arteriosus of prematurity. Arch Dis Child 1991;66:55–58. 29. Tammela O, Ojala R, Livainen T, et al. Short versus prolonged indomethacin therapy for patent ductus arteriosus in preterm infants. J Pediatr 1999;134:552–557. 30. Fowlie P. Prophylactic indomethacin: systematic review and meta-analysis. Arch Dis Child 1996;74:F81–F87. 31. Clyman R. Recommendations for the postnatal use of indomethacin: an analysis of four separate treatment strategies. J Pediatr 1996;128:601–607. 32. Van Overmeire B, Follens I, Hartmann S, Creten W, Van Acker K. Treatment of patent ductus arteriosus with ibuprofen. Arch Dis Child 1997;76: F179–F184.
Drugs
Drugs used in prematurity
J. McIntyre and S. Conroy
neonatal intensive care. Surfactant replacement reduces the risk of a baby with RDS dying by 40% and the risk of pneumothorax by 30–70%.1, 2 Combining postnatal surfactant and antenatal steroids is more effective than either treatment alone.3 The giving or withholding of surfactant based on arbitrary gestational or weight limits is not supported by the data available, with even the smallest of babies showing some benefit.4, 5 Since surfactant undoubtedly improves the outlook for ventilated babies the focus of debate has shifted to what product (natural vs synthetic) and when to give it (prophylaxis vs rescue).
INTRODUCTION The aim of this article is to introduce the reader to some important and common drugs used in neonatal intensive care units (NICUs). Drugs are an integral part of intensive care and impact on many aspects of managing the sick newborn. However, selecting which drug to use, when to use it, at what dose and for how long is far from straightforward. The choice is bewildering; there are large variations in size of infants and drug handling capacity, and for an individual there will be marked changes in these parameters during a stay on NICU. By focusing on some key areas we hope to give insight into current practice and the therapeutic dilemmas in using drugs in the newborn. The following topics will be considered: • • • • • •
Natural versus synthetic There are four licensed surfactants for use in the UK, two synthetic and two derived from animal sources (see Table 1). Animal-derived surfactants have a more rapid onset of action. Studies comparing natural and synthetic surfactants have usually involved Survanta and Exosurf. Meta-analyses of suitable studies suggest a reduced pneumothorax rate and a trend towards reduced mortality in the natural group.6 However, it would take large comparative trials to resolve which is better.2
Surfactant Antibiotics Steroids Anticonvulsants Analgesics Indomethacin.
SURFACTANT Surfactant is a complex mixture of phospholipids, neutral lipids and specific proteins. It is synthesized and stored in alveolar type II cells. It reduces surface tension in the alveoli so easing expansion and reducing the tendency to atelectasis. Exogenous surfactant to treat neonatal respiratory distress syndrome (RDS) has been a major advance in
Prophylaxis versus rescue Randomized controlled trials show surfactant treatment given once a preterm baby is intubated (prophylaxis) is more effective than treatment a few hours later (rescue).7 Prophylaxis reduced mortality with an odds ratio (and 95% confidence intervals) of 0.55 (0.41–0.73). There were similar improvements in incidence of air leak syndromes. Overall, prophylactic treatment would save about seven more lives than rescue treatment for every 100 babies treated.
J. McIntyre, Senior Lecturer in Child Health, S. Conroy, Lecturer in Paediatric Clinical Pharmacy, Derbyshire Children’s Hospital, University of Nottingham, Derby, UK.
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Table 1 Surfactants licensed for use in the UK Name
Source
Dose
Volume
Cost
Poractant alfa (Curosurf)
Porcine
1.2 ml/kg
£400.00 for 1.5 ml vial
Beractant (Survanta)
Bovine
4 ml/kg
£306.43 for 8 ml vial
Pumactant (ALEC)
Synthetic
1.2 ml
£150.00 per vial
Colfosceril (Exosurf)
Synthetic
100 mg/kg+ two further doses at 12 and 24 h if necessary 100 mg/kg up to maximum of four doses in 48 h 100 mg repeated at 1 and 24 h 67.5 mg/kg repeated at 12 and 24 h
5 ml/kg
£306.43 for 8 ml vial
Other indications Other conditions occurring in the neonatal period can result in a secondary deficiency of surfactant. Exogenous surfactant may therefore have a role in conditions such as meconium aspiration syndrome, pneumonia, pulmonary haemorrhage or where pulmonary hypoplasia is a complicating factor e.g. in congenital diaphragmatic hernia.
Prompt treatment of sepsis is essential to avoid rapid deterioration. Most units in the UK use a combination of a broad-spectrum penicillin or cephalosporin with an aminoglycoside antibiotic e.g. benzylpenicillin and gentamicin as first line therapy for likely or suspected infection. These will usually be given for 48 h until culture results are known, then stopped if cultures are negative. With positive cultures, antibiotic choice can be adjusted in light of sensitivity results.
ANTIBIOTICS Bacterial infections are a major cause of morbidity and mortality in NICU. The incidence of neonatal sepsis ranges from 1 to 10 per 1000 live births worldwide. Despite advances in antibiotic therapy, mortality remains high at 20–30%.8 The major pathogens in the first few days of life are usually maternally transmitted and include Group B Streptococcus, Escherichia coli, enterococci and Listeria monocytogenes. Haemophilus influenzae is also important in preterm babies. Prophylactic antibiotics to cover these organisms are used for babies with risk factors for infection such as: • maternal membranes ruptured more than 24 h predelivery; • unexplained maternal pyrexia; • known recent Group B Strep. cultured in HVS; • umbilical catheterization more than 24 h after birth; • suspected Listeria infection in ill baby with stained liquor; • babies showing rapid unexplained deterioration. Nosocomial late onset infections occur in up to 60% of infants in NICU.9 Coagulase-negative staphylococci e.g. Staph. epidermidis are important pathogens where umbilical and central catheters are in situ. Pseudomonas, Klebsiella and Serratia spp. are other potential infecting organisms. Very low birth weight babies are particularly susceptible to nosocomial infections resulting in septicaemia, meningitis and pneumonia, with approximately 18% of babies under 1500 g being affected.10
Penicillins Benzylpenicillin is active against most streptococci (including Group B Strep.). It is eliminated mainly by the kidney. Since renal function is immature in the neonate, particularly the preterm neonate, doses are adapted to compensate for reduced excretion, and subsequently adjusted with increasing postnatal age and renal function. Ampicillin is preferred in some centres and is the drug of choice if Listeria infection is likely. Flucloxacillin and an aminoglycoside are a combination used by many centres for initial treatment of late onset infection. Aminoglycosides Gentamicin, netilmicin or tobramycin may be used. These are primarily active against aerobic Gramnegative bacilli. Glomerular filtration is the major route of excretion. As with all renally excreted drugs, doses must be adjusted to compensate for the immaturity of the neonatal kidney. These drugs are highly water soluble, with a large volume of distribution in the newborn. Therapeutic drug monitoring (TDM) is necessary to ensure effective, non-toxic serum concentrations. Renal function increases with gestational age, postnatal age, weight and the use of antenatal steroids. It is decreased by the pre- or postnatal use of indomethacin, perinatal asphyxia and the presence of a persistent ductus arteriosus. Protocols for aminoglycoside dosing attempt to account for these variables. Work is ongoing to establish ideal dose schedules for safe and effective therapy. Achieving therapeutic peak
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serum concentration in the first 24 h of therapy is associated with improved outcomes in adults. The importance of this in neonates is not clear, but loading doses or high doses given at extended dose intervals to compensate for the large volume of distribution and reduced capacity for excretion may be the way forward. Nephrotoxicity and ototoxicity are major sideeffects in adult patients. Nephrotoxicity seems to be less common in the neonate, but controversy remains regarding the incidence of ototoxicity since this can be compounded by many other factors such as prematurity itself, meningitis and intracranial haemorrhage. Cephalosporins Third generation cephalosporins including cefotaxime and ceftazidime are active against the major neonatal pathogens including Group B Strep. and Gramnegative bacilli such as E. coli. They are widely used in the treatment of neonatal meningitis. Cefotaxime is rapidly metabolized by esterase action in the liver, erythrocytes and other tissues. Its half-life is inversely related to gestational and postnatal age. Ceftazidime is eliminated primarily renally in unchanged form. Due to the reduced nephrotoxicity of cephalosporins compared to aminoglycosides some units use a combination of a penicillin and a cephalosporin. This avoids the need for blood sampling for TDM. Glycopeptides Vancomycin is a glycopeptide antibiotic active against Gram-positive bacteria including multidrugresistant strains. The recent increase in infections due to methicillin-resistant coagulase-negative Staph. aureus (MRSA) has resulted in an important role for vancomycin in NICU.11 It is renally eliminated unchanged. Dosage recommendations vary but are based on factors highlighted above. TDM is generally recommended but there is debate regarding the need for this.11 It is nephrotoxic but rarely ototoxic in the neonate. Concomitant administration with aminoglycosides significantly increase nephrotoxicity. Teicoplanin is better tolerated, its longer half-life allows it to be given less frequently and TDM is unnecessary. Metronidazole Metronidazole is active against anaerobic bacteria and is frequently used to treat necrotizing enterocolitis (NEC). Doses of all these drugs vary in different NICUs due to lack of clear evidence. The introduction of Medicines for Children12 may go some way towards standardization in the UK.
DEXAMETHASONE Chronic lung disease (CLD) or bronchopulmonary dysplasia (BPD) is characterized by the need for prolonged mechanical ventilation or oxygen accompanied by specific chest X-ray changes. It develops in 30–40% of infants <1500 g ventilated for RDS and is a significant cause of morbidity. Various strategies and drug treatments have been tried to reduce the incidence and severity of CLD. Dexamethasone has been widely used in a prophylactic role and for therapy in established CLD. The improvement in respiratory status seen after dexamethasone may involve a number of mechanisms such as a reduction in pulmonary oedema, increased surfactant production, enhanced adrenergic activity and inhibition of prostaglandin and leucotrine synthesis. In the Collaborative Dexamethasone Trial it was used to treat infants with established CLD at around 3 weeks of age.13 Active treatment significantly reduced the duration of further assisted ventilation (median days for survivors 11 vs 17.5) but there was no difference in total time of oxygen dependence or length of hospital stay. Facilitation of early extubation attracts many to use dexamethasone earlier in the course of CLD. However, initiating treatment at 2 weeks compared with starting at 4 weeks was found to be more hazardous and no more beneficial.14 A systematic review of late postnatal corticosteroids for CLD showed no effect on mortality or most other outcomes and concluded that the benefits of late corticosteroid therapy may not outweigh the actual or potential adverse outcomes.15 Early dexamethasone to prevent CLD has also attracted much interest. Dexamethasone may help limit the early inflammatory responses seen in the lungs of ventilated infants, a process thought to contribute to CLD. A 12-day course of dexamethasone in ventilated infants <1600 g and started within 36 h of birth did not decrease the incidence of CLD and/or death; however, it did appear to reduce oxygen dependency at 36 weeks after conception.16 A recent systematic review and meta-analysis of early postnatal dexamethasone for prevention of chronic lung disease found that dexamethasone started between 7 and 14 days of age reduced mortality and chronic lung disease.17 Despite widespread use and short-term benefits in lung function there are significant side-effects, such as hyperglycaemia, bacteraemia, hypertension and impaired growth.14, 15, 17 Infants may also be at risk of other potential adverse effects such as gastrointestinal perforation, severe retinopathy of prematurity, necrotizing enterocolitis and intraventricular haemorrhage, although studies to date have not confirmed a significant increase in these events. A particular area of concern that awaits more data is that early dexamethasone may have adverse effects on neurodevelopmental outcome.
Drugs used in prematurity ANTICONVULSANTS The incidence of neonatal seizures is about 2.6 per 1000 live births, with increased rates in preterm infants.18 Management of seizures requires identifying and treating the underlying condition (e.g. infection, intracranial bleeds, metabolic disorders, hypoxia ischaemia, developmental defects and drug withdrawal) and control of the seizures. Seizures have a number of harmful effects (e.g. increased cerebral metabolism, hypoxia, hypercarbia and hypertension) and quick effective control is essential to minimize further cerebral injury. Drug treatment takes place alongside general supportive measures to ensure adequate ventilation and perfusion. The usual sequence of therapy is phenobarbitone, phenytoin and benzodiazepines.19 Phenobarbitone For acute treatment the properties of phenobarbitone can be helpful: it enters CSF rapidly and efficiently; the blood level is predictable from the dose given; intravenous, intramuscular and oral routes are available.19 A loading dose of phenobarbitone at 20 mg/kg with additional doses up to a total of 40 mg/kg can achieve seizure control in up to 70% of infants.20 Phenobarbitone is also used for maintenance therapy. Because of its long half-life, once-daily dosing can be adequate. However, its liver enzyme inducing properties mean a dose increment may be required a few weeks after starting treatment. Phenytoin Phenytoin (20 mg/kg intravenously) is often used acutely if seizures persist after loading with phenobarbitone. It has to be given slowly to avoid cardiac arrhythmias and is an irritant to veins. However, maintenance therapy is difficult because of its zero order kinetics, whereby a small increase in dose can result in large increases in blood concentrations due to saturation of the enzyme responsible for its metabolism. Careful monitoring and attention to blood levels is essential. Benzodiazepines Benzodiazepines are effective anticonvulsants. In the newborn they are used as second or third line treatments for acute seizures. Lorazepam has potential advantages over diazepam in that it has an equally rapid onset of action (usually 2–3 min) but is not so rapidly redistributed from the brain giving a longer duration of action. Clonazepam may be equally effective. ANALGESICS Neonates, both preterm and term, feel pain. In the NICU there are numerous painful procedures such
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as venous and arterial cannulation, heel pricks, intubation, lumbar puncture and chest drain insertion. Disease states such as necrotizing enterocolitis are also painful. Surgical procedures require adequate intra- and post-operative analgesia. Repeated painful events in the NICU can have detrimental effects on the newborn’s clinical state and may contribute to complications such as intraventricular haemorrhage or periventricular leukomalacia.21 Despite this recognition a neonate is less likely to receive analgesia for a painful procedure than an older child.22 Pain assessment Assessing neonatal pain uses a variety of methods such as measurement of physiological parameters (e.g. increases in heart rate, respiratory rate, blood pressure, palmar sweating), stress hormones (e.g. changes in adrenaline, noradrenaline, cortisol concentrations) and behavioural changes (e.g. facial expression, body movements and cry). It is essential that a valid pain assessment tool be used to monitor the efficacy of analgesia administered and to aid development of appropriate analgesic protocols.23 Topical anaesthesia The two most commonly used topical anaesthetics in children are EMLA cream (Astra) and Ametop (Smith and Nephew). They are not licensed for use in neonates although interest is growing in this area. Fears of methaemaglobinaemia in the neonate caused by the prilocaine component of EMLA are now thought to be unfounded.24 Morphine For relief of severe pain and to facilitate ventilation, morphine is the opiate with which there is most experience in neonatal patients and the most in-depth understanding of the pharmacokinetics of the drug. A loading dose is necessary to obtain appropriate initial serum concentrations followed by continuous intravenous infusion. Respiratory depression, urinary retention and constipation may occur and patients must be closely monitored. However, neonates should not be deprived of the benefits of this drug due to fears of side-effects. Paracetamol Although neonates metabolize paracetamol by a different route compared to older children and adults, mainly by sulphation rather than glucuronidation, it has been shown to be safe and can be used when a mild analgesic or anti-pyretic is required.
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Other measures Several studies have documented the analgesic effects of concentrated sucrose and glucose solutions in newborn babies undergoing minor procedures. It has been suggested that a pacifier in conjunction with these solutions may have a synergistic analgesic effect.25 This may however be frowned upon in units with a strong breast-feeding policy.
INDOMETHACIN Shortly after birth, physiological processes usually effect prompt functional closure of the ductus arteriosus. Precise mechanisms are incompletely understood but it is known that constriction of the ductus arteriosus can be inhibited by prostaglandin E and promoted by inhibiting prostaglandin synthesis. The focus of this discussion is the preterm infant where persistent ductus arteriosus (PDA) has different management implications from PDA in term infants. The incidence of PDA in preterm babies with RDS is about 40% on day 3 of life.26 The undesirable consequences of left to right shunting of blood through a PDA include increased pulmonary blood flow, increased cardiac workload and reduced renal and gastrointestinal blood flow. There is also increased risk of intraventricular haemorrhage and chronic lung disease. Indomethacin, a prostaglandin synthetase inhibitor, has been used for pharmacological closure of a PDA for over 20 years. Success in achieving initial closure is about 80–90% but after stopping treatment relapse rate may be around 20–40%.27–29 However, there are potential complications such as altered platelet and renal function and decreased cerebral, mesenteric and renal blood flow. Various regimes have been evaluated e.g. short course (1–2 days) versus long course (6–7 days) and early prophylaxis versus late symptomatic.30, 31 A prolonged low dose of indomethacin (0.1 mg/kg daily for 6 days) resulted in a greater initial closure rate of PDA, lower reopening rate and fewer infants experiencing a rise in serum creatinine or urea compared with a short course (0.2 mg/kg 12 hourly for three doses).28 However, more recent studies have found no advantage of prolonged low dose regimes compared with short courses.29 The role of prophylactic indomethacin has also been addressed.30 For small babies <1750 g, indomethacin within 24 h had some short-term benefits: a lower incidence of symptomatic PDA and a reduction in grade 3/4 intraventricular haemorrhage. Although there appeared to be a trend to overall reduced mortality in treated infants, respiratory outcomes were similar and there was also a trend to increased incidence of necrotizing enterocolitis. The effect on long-term neurological outcome is not known. Clearer understanding of long-term outcomes and adverse effects is required before routine prophylactic indomethacin becomes established.
The clinical benefits of pharmacological closure of the PDA and the wish to reduce side-effects has led to the evaluation of other agents. Of particular interest is ibuprofen which seems to be as effective as indomethacin but with fewer renal side-effects.32
SUMMARY Drug selection is just one of the many challenges in caring for the newborn infant, especially the extremely small premature baby delivered at the edges of viability. Specific conditions are occurring at a time of unique physiological adaptations. Knowledge of these processes needs to be combined with understanding of basic pharmacological principles if drugs are to be used safely and effectively. Continuing questioning and evaluation of our therapeutic interventions is required to ensure the best practice is established. REFERENCES 1. Halliday H. Surfactant therapy in neonates. Paed Perinatal Drug Therapy 1997;1:30–40. 2. Sweet D, Halliday H. Surfactant therapy. Curr paediatrics 1998;8:103–107. 3. Jobe A, Mitchell B, Gunkel J. Beneficial effects of the combined use of prenatal corticosteroids and postnatal surfactant on preterm infants. Am J Obstet Gynecol 1993;168:508–513. 4. American Exosurf Neonatal Study Group. Controlled trials of a single dose of synthetic surfactant at birth in premature infants weighing 500–699 grams. J Pediatr 1992;120:S3–S12. 5. Ten Centre Study Group. Ten centre trial of artificial surfactant (artificial lung expanding compound) in very premature infants. BMJ 1987;294:991–996. 6. Soll R. Natural surfactant extract vs synthetic surfactant in the treatment of established respiratory distress syndrome (Cochrane review). Update Software, 4th edn, 1998. 7. Morley C. Systematic review of prophylactic vs rescue surfactant. Arch Dis Child 1997;77:F70–F74. 8. Fanos V, Dall’ Agnola A. Antibiotics in neonatal infections: a review. Drugs 1999;58:405–427. 9. Fowlie P, Gould C, Parry G, Phillips G, Tarnow-Mordi W. CRIB (clinical risk index for babies) in relation to nosocomial bacteraemia in very low birthweight or preterm infants. Arch Dis Child 1996:F49–F52. 10. Van den Anker J. Antibiotics in neonates. Paed Perinatal Drug Therapy 1997;1:41–45. 11. Grimsley C, Thomson A. Pharmokinetics and dose requirements of vancomycin in neonates. Arch Dis Child 1999;F221–F227. 12. Medicines for Children. London: Royal College of Paediatrics and Child Health, 1999. 13. Collaborative Dexamethasone Trial Group. Dexamethasone therapy in neonatal chronic lung disease: an international placebo-controlled trial. Pediatrics 1991;88:421–427. 14. Papile LA, Tyson JE, Stoll BJ, et al. A multicenter trial of two dexamethasone regimens in ventilator-dependent premature infants. N Engl J Med 1998;338:1112–1118. 15. Halliday H, Ehrenkranz R. Delayed (>3 weeks) postnatal corticosteroids for chronic lung disease in preterm infants. The Cochrane Library 1999;3. 16. Tapia JL, Ramirez R, Cifuentes J, et al. The effect of early dexamethasone administration on bronchopulmonary dysplasia in preterm infants with respiratory distress syndrome. J Pediatr 1998;132:48–52. 17. Bhuta T, Ohlsson A. Systematic review and meta-analysis of early postnatal dexamethasone for prevention of chronic lung disease. Arch Dis Child 1998;79:F26–F33.
Drugs used in prematurity 18. Ronen G, Penney S, Andrews W. The epidemiology of clinical neonatal seizures in Newfoundland: a population-based study. J Pediatr 1999;134:71075. 19. Volpe J. Neonatal seizures. In: Neurology of the newborn. 3rd edn. London: W.B. Saunders, 1995:172–207. 20. Gilman J, Gal P, Duchowny M, Weaver R, Ransom J. Rapid sequential phenobarbital treatment of neonatal seizures. Pediatrics 1989;83:674–678. 21. Anand K, McIntosh N, Lagercrantz H et al. Analgesia and sedation in preterm neonates who require ventilatory support: results from the NOPAIN trial. Neonatal outcome and prolonged analgesia in neonates. Arch Ped Adol Med 1999;153:331–338. 22. Bauchner H, May A, Coates E. Use of analgesic agents for invasive medical procedures in pediatric and neonatal intensive care units. J Pediatr 1992;121:647–649. 23. Choonara I. Pain in neonates, assessment and management. Semin Neonatol 1998;3:137–142. 24. Rutter N. Topical local anaesthesia in the newborn. Paed Perinatal Drug Therapy 1997;1:20–24. 25. Carbajal R, Chauvet X, Chouderc S, Olivier-Martin M. Randomised trial of analgesic effects of sucrose, glucose and pacifiers in term neonates. BMJ 1999;319:1393–1396.
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26. Ellison R, Peckham G, Lang P, Talner N, Lerer T, Lin L. Evaluation of the pretem infant for patent ductus arteriosus. Pediatrics 1983;71:364–372. 27. Couser R, Ferrara B, Wright G, et al. Prophylactic indomethacin therapy in the first twenty-four hours of life for the prevention of patent ductus arteriosus in preterm infants treated prophylactically with surfactant in the delivery room. J Pediatr 1996;128:631–637. 28. Rennie J, Cooke R. Prolonged low dose indomethacin for persistent ductus arteriosus of prematurity. Arch Dis Child 1991;66:55–58. 29. Tammela O, Ojala R, Livainen T, et al. Short versus prolonged indomethacin therapy for patent ductus arteriosus in preterm infants. J Pediatr 1999;134:552–557. 30. Fowlie P. Prophylactic indomethacin: systematic review and meta-analysis. Arch Dis Child 1996;74:F81–F87. 31. Clyman R. Recommendations for the postnatal use of indomethacin: an analysis of four separate treatment strategies. J Pediatr 1996;128:601–607. 32. Van Overmeire B, Follens I, Hartmann S, Creten W, Van Acker K. Treatment of patent ductus arteriosus with ibuprofen. Arch Dis Child 1997;76: F179–F184.