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Supplementary material B: Archived monographs 

Supplementary material B: Archived monographs

Sean Ainsworth

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date: 13 June 2021



Neonatal use of acetazolamide declined considerably once it was realized that it did more harm than good when used to treat post-haemorrhagic hydrocephalus.

It may still be encountered in the treatment of maternal glaucoma, but neonatal glaucoma is usually treated topically with eye drops or surgically.


Acetazolamide is a specific inhibitor of the enzyme carbonic anhydrase used to decrease cerebrospinal (CSF) fluid in children with idiopathic intracranial hypertension and ocular fluid production in children with glaucoma. It has also been used less widely as an anticonvulsant (particularly with petit mal and complex partial seizures in children). Its first clinical use, in 1952, was as a diuretic because it increases the renal loss of bicarbonate (and hence sodium, potassium and water). It is excreted unchanged in the urine with a serum half-life of four to ten hours.

Acetazolamide is a sulphonamide derivative, and complications such as agranulocytosis, thrombocytopenia, aplastic anaemia, skin toxicity, and crystalluria with calculus formation have all been reported on occasion.

Fetal and infant implications of maternal treatment

Acetazolamide crosses the placenta and has been reported to cause limb defects in rodents. Similar defects have not been reported in humans and use during pregnancy for glaucoma, intracranial hypertension, and altitude sickness has not shown any other adverse effects on either the fetus or the infant. Acetazolamide is not concentrated in the milk, and the neonate receives less than 0.5% of the maternal dose, therefore it is generally considered compatible with breastfeeding.

Post-haemorrhagic hydrocephalus

Regular tapping, to remove cerebrospinal fluid (CSF), was commonly used to reduce intracranial pressure but sometimes caused iatrogenic meningitis. Consequently, oral acetazolamide (which reduced CSF production) was used with increasing frequency over a 25-year period in the hope that it would postpone or abolish the need for surgical intervention. In 1998, a UK-based trial (using acetazolamide 32 mg/kg eight hourly and furosemide 500 microgram/kg 12 hourly) was stopped when it was found that not only did treatment not reduce the requirement for shunt placement but it significantly increased the number (84% versus 60%) who either died or who were disabled at one year. Isosorbide (see similar archived monograph) was also used in much the same way for some years but was never the subject of controlled trial evaluation.

If regular tapping is necessary to keep CSF pressure below 7 cm H20, insertion of a ventricular reservoir should allow the atraumatic and safe removal of CSF until such time as growth and a reduction in the CSF protein content makes the insertion of a formal shunt possible.

Doses used in various treatments


Given at a dose of 4 mg/kg by mouth (or, slowly, by intravenous injection) once every eight hours. Some infants only respond to two-and-a-half times this dose.


Neonatal glaucoma is rare and should always be managed by a specialist. Topical treatment with β‎-blocker or a prostaglandin analogue is the treatment of choice, if that fails surgery is usually considered. Rarely, is it necessary to use acetazolamide but 4–10 mg/kg orally eight hourly has been used.

Idiopathic intracranial hypertension:

An initial dose of 8 mg/kg by mouth once every eight hours would be used. On occasion it would be necessary to give three times as much as this to reduce CSF production.

Electrolyte imbalance

In some cases, acetazolamide causes hypokalaemic acidosis and gastrointestinal disturbances. The acidosis could be countered by giving 4 mmol/kg of sodium bicarbonate prophylactically once a day by mouth with high-dose treatment to reduce this risk. It was necessary to monitor electrolytes since a dangerous metabolic acidosis can occur if there is renal failure. It was sometimes necessary to give 1 mmol/kg a day of potassium chloride as an oral supplement.

Supply and administration

Acetazolamide was supplied as 500 mg vials for injection. The dry powder would be reconstituted with 5 mL of sterile water. A single mL of the reconstituted solution would be diluted to 12.5 mL with glucose or glucose/sodium chloride to obtain a solution for oral use containing 8 mg/mL. This solution should not be kept more than 24 hours after reconstitution even if kept at 4 ºC. The same preparation could be given intravenously where necessary as long as it was used promptly after reconstitution.

A sugar-free oral suspension with a four-week shelf life could be prepared by some pharmacies on request.


Carrion E, Hertzog JH, Medlock MD, et al. Use of acetazolamide to decrease cerebrospinal fluid production in chronically ventilated patients with ventriculopleural shunts. Arch Dis Child 2001;84:68–71.Find this resource:

Kennedy CR, Ayers S, Campbell MJ, et al. Randomized, controlled trial of acetazolamide and furosemide in posthemorrhagic ventricular dilatation in infancy: follow-up at 1 year. Pediatrics 2001;108:597–607. [RCT]Find this resource:

Maertzdorf WJ, Vles JSH, Beuls E, et al. Intracranial pressure and cerebral blood flow velocity in preterm infants with posthaemorrhagic ventricular dilatation. Arch Dis Child Fetal Neonatal Ed 2002;87:F185–8.Find this resource:

Matthews YY. Drugs used in childhood idiopathic or benign intracranial hypertension. Arch Dis Child Educ Pract Ed 2008;93:19–25.Find this resource:

Whitelaw A. Intraventricular haemorrhage and posthaemorrhagic hydrocephalus: pathogenesis, prevention and future interventions. Semin Perinatol 2001;6:135–46.Find this resource:

Whitelaw A, Aquilina K. Management of posthaemorrhagic ventricular dilatation. Arch Dis Child Fetal Neonatal Ed 2012;97:F229–3.Find this resource:

See also the Cochrane reviews of ventriculomegaly management

Whitelaw A, Kennedy CR, Brion LP. Diuretic therapy for newborn infants with posthemorrhagic ventricular dilatation. Cochrane Database Syst Rev 2001;2:CD002270. Available at: this resource:

Whitelaw A, Lee-Kelland R. Repeated lumbar or ventricular punctures in newborns with intraventricular haemorrhage. Cochrane Database Syst Rev 2017;4:CD000216. Available at: this resource:



Aztreonam could be useful in the management of Gram-negative bacterial infections, showing few of the potentially toxic side effects seen when aminoglycosides are prescribed.


Aztreonam is a narrow-spectrum monocyclic β‎-lactam (‘monobactam’) antibiotic first introduced in 1985 which is only active against Gram-negative aerobic bacteria. It is bactericidal, acting to inhibit bacterial cell wall synthesis. Unfortunately, aztreonam resistance is emerging as the result of extended-spectrum β‎-lactamases (ESBLs). These are a rapidly evolving group of β‎-lactamases which share the ability to hydrolyse third-generation cephalosporins as well as aztreonam.

Notwithstanding this, aztreonam remained useful in the treatment of Pseudomonas infection, a property it shares with ceftazidime (q.v.), and was sometimes been used in conjunction with an aminoglycoside in the management of Pseudomonas infection because of synergy in vitro. It was also of value in the management of Haemophilus influenzae (including ampicillin resistant and other penicillinase producing strains), Enterobacter, Klebsiella, Neisseria, and Proteus species.

Aztreonam is widely distributed in most body fluids, including bile, urine, and bronchial secretions, and diffuses into the CSF relatively well when the meninges are inflamed. It is partially metabolized to an inactive metabolite SQ-26992 (which has a long half-life) but is mostly excreted in the urine by a combination of glomerular filtration and tubular secretion. The half-life is, as a consequence, four times as long at birth as it is in adults (6.5 versus 1.7 hours), changing progressively in the first few months of life. Coliform organisms have become increasingly resistant to aztreonam in some parts of the world, including the Indian sub-continent, in the last ten years.

Hypersensitivity reactions can occur, including skin rashes and urticaria. Caution should be observed in giving the drug to patients who are hypersensitive to penicillin, but there seems to be little cross-reactivity with sensitivity to other β‎-lactam antibiotics.

Fetal and infant implications of maternal treatment

There is no evidence of teratogenicity, but the manufacturer has never recommended its use during pregnancy (or its use in babies less than one week old). The baby ingests less than 1% of the maternal dose (on a weight-adjusted basis) if the mother is treated with aztreonam during lactation. Furthermore, absorption from the gastrointestinal tract is, in any case, limited.


It was usual to give 30 mg/kg intravenously (or intramuscularly) once every 12 hours in the first week of life, every eight hours in babies one to three weeks old, and every six hours in babies older than this. The dose would be halved in babies with renal failure.

Supply and administration

Vials containing 1 gram of aztreonam powder for reconstitution were available. These would be reconstituted by adding at least 3 mL of water for injection. The infusion would then be made to a volume of 50 mL by adding to glucose 5% or 0.9% sodium chloride to give a final concentration of 20 mg/mL.

This final solution would be given at a dose of 1.5 mL for every kilogram the baby weighed over 20–60 minutes.


Bosso JA, Black PG. The use of aztreonam in pediatric patients: a review. Pharmacotherapy 1991;11:20–5.Find this resource:

Cuzzolin L, Fanoe V, Zamreri D, et al. Pharmacokinetics and renal tolerance of aztreonam in premature infants. Antimicrob Agents Chemother 1991; 35:1726–8.Find this resource:

Huang Y, Zhuang S, Du M. Risk factors of nosocomial infection with extended-spectrum beta-lactamase-producing bacteria in a neonatal intensive care unit in China. Infection 2007;35:339–45.Find this resource:

Iqbal M, Patel IK, Shah SH, et al. Susceptibility patterns of Escherichia coli: prevalence of multidrug-resistant isolates and extended spectrum beta-lactamase phenotype. J Pak Med Assoc 2002;52:407–11.Find this resource:

Isaacs D. Unnatural selection: reducing antibiotic resistance in neonatal units. Arch Dis Child Fetal Neonatal Ed 2006;91:F72–4Find this resource:

Ito K, Hirose R, Tamada Y, et al. Pharmacokinetic and clinical studies on aztreonam in the perinatal period. Jpn J Antibiot 1990;43:719–26.Find this resource:

Liikitnukul S, McCracken GH, Threlkeld N, et al. Pharmacokinetics and plasma bactericidal activity of aztreonam in low-birth-weight infants. Antimicrob Agents Chemother 1987;31:81–3.Find this resource:

Samaha-Kfoury JN, Araj GF. Recent developments in beta lactamases and extended spectrum beta lactamases. Brit Med J 2003;327:1209–13.Find this resource:

Umaña MA, Odio CM, Castro E, et al. Evaluation of aztreonam and ampicillin vs amikacin and ampicillin for treatment of neonatal bacterial infections. Pediatr Infect Dis J 1990;9:175–80.Find this resource:



Bromocriptine used to be used to treat galactorrhoea and cyclical benign breast disease. It was widely used for many years to suppress lactation after childbirth, but its use for this purpose is now discouraged.


Bromocriptine mesylate is a semi-synthetic ergot derivative which acts as a dopamine receptor agonist. It functions like a prolactin inhibitory factor in the hypothalamus to stimulate inhibitory dopamine receptors. Treatment results in inhibition of prolactin release and a modest stimulation of growth hormone release (although, paradoxically it inhibits growth hormone release in acromegaly for reasons that are not entirely clear).

The drug is 90% absorbed when given by mouth. It is metabolized by the liver with a half-life of two to three days, and excreted largely in the bile. It first came into general use for the management of Parkinson’s disease in 1974 (although it is now only used in patients who do not respond to levodopa).

Fetal and infant implications of maternal treatment

Bromocriptine was mainly used in the treatment of prolactinomas (a pituitary tumour), and of hyperprolactinaemia causing amenorrhoea. Fertility and cyclical ovarian function are usually restored within two months. Multiple ovulations were not reported. The drug was stopped at once if pregnancy occurs (though there are no reported cases of malformation). If hyperprolactinaemia is associated with the presence of a prolactinoma there is a risk of visual field defects developing during pregnancy because of tumour enlargement.

Effect on lactation

Milk formation during late pregnancy occurs under the combined stimulus of oestrogens, prolactin (placental lactogen), and progesterone. Insulin and cortisol may also have a role. Oestrogens antagonize the effects of prolactin on milk secretion and lactation is stimulated when oestrogen levels fall after delivery. Oestrogens were once used widely to suppress lactation in the puerperium, but they were found to be relatively ineffective, and to increase the risk of potentially life-threatening thromboembolism.

Trials undertaken between 1972 and 1984 then showed bromocriptine to be a more effective alternative. However, most drug trials only looked at the immediate effect of drug treatment and whilst there was some evidence that bromocriptine reduces pain, engorgement, and milk production one week after delivery more than a breast binder (the other commonly used treatment at the time), the situation was reversed two weeks later.

Latterly, reports appeared of mothers having seizures, strokes, heart attacks, and sudden severe hypertension while taking bromocriptine to suppress lactation. It is difficult to know whether these problems were solely caused by the use of bromocriptine but the problems were, however, reported with sufficient frequency for the manufacturers to stop recommending the use of bromocriptine to suppress lactation in 1994.

Since breast engorgement and discomfort is only a transient problem there can seldom be a case for using any drug to suppress lactation in most mothers, but its use may still, perhaps, be justified in certain situations. Continued milk production can certainly cause acute anguish to a few mothers coping with a stillbirth or early neonatal death. It was advised that if bromocriptine was used for suppression of lactation, treatment should be stopped at once if the mother experienced any severe headache or visual disturbance.

Cabergoline (q.v.) is a more recently introduced analogue with a longer half-life. It seems to be relatively free from the problems associated with bromocriptine to suppress lactation. The absence of such adverse effects may be, in part, because it has been less widely used. Quinagolide, a related dopamine agonist, has not been used for this purpose.


A single 2.5 mg dose of bromocriptine would be given on day 1 to prevent lactation or, if lactation has already begun, 2.5 mg a day for two to three days might be used to suppress lactation. The dose in both cases would be increased to 2.5 mg twice a day for two weeks.

Milk production almost always increased again for a time after treatment is stopped.


Bromocriptine was supplied as 2.5 mg tablets.


Dutt S, Wong F, Spurway JH. Fatal myocardial infarction associated with bromocriptine for postpartum lactation suppression. Aust NZ J Obstet Gynaecol 1998;38:116–19.Find this resource:

European Multicentre Study Group for Cabergoline in Lactation Inhibition. Single dose cabergoline versus bromocriptine in inhibition of puerperal lactation: randomised, double-blind, multicentre study. Brit Med J 1991;302:1367–71. [RCT]Find this resource:

Morgans D. Bromocriptine and postpartum lactation suppression. Br J Obstet Gynaecol 1995;102:851–3.Find this resource:

Webster J. A comparative review of the tolerability profiles of dopamine agonists in the treatment of hyperprolactinaemia and inhibition of lactation. Drug Safety 1996;14:228–38.Find this resource:

See also the relevant Cochrane review

Oladapo OT, Fawole B. Treatments for suppression of lactation. Cochrane Database Syst Rev 2012;9:CD005937. Available at : this resource:



Cefoxitin sodium was a broad-spectrum second-generation cephalosporin with enhanced activity against anaerobic bacteria. It is no longer marketed in the United Kingdom and most of Europe but remains available in North America and other countries. It was formerly used prophylactically, like ampicillin (q.v.), in patients undergoing abdominal surgery and, on its own, in the routine postoperative care of children with a ruptured appendix.


Cephalosporins are all N-acylated derivatives of 7-β‎-aminocephalosporanic acid with a β‎-lactam ring fused to a six-membered dihydrothiazine ring, first found amongst fermentation products from Acremonium chrysogenum (Cephalosporium acremonium). A wide range of semi-synthetic products have been produced since 1948. First-generation products rapidly gave way to products with greater resistance to the β‎-lactamase enzymes that could be given parenterally. Most of these have now given way to third- and fourth-generation products with enhanced antibacterial activity; a few, however, are still used for specialized purposes.

Cefoxitin retained its utility because of its ability to control anaerobic infection, and a better than average activity against Bacteroides fragilis. Most Gram-positive cocci are moderately susceptible, but Pseudomonas species and Listeria monocytogenes are resistant, as are enterococci and Enterobacter. Cerebrospinal fluid (CSF) penetration is poor. It is rapidly eliminated by the kidneys with a neonatal half-life (three to four hours) that is nearly four times as long as in adults. Problems associated with treatment are uncommon but are largely the same as for all cephalosporins (see monograph on ceftazidime).

Fetal and infant implications of maternal treatment

Use was considered safe during pregnancy and lactation. There is no evidence of teratogenicity, and the baby ingests less than 1% of the weight-related dose if the mother takes the drug while breastfeeding (little of which would be absorbed anyway).

Caesarean delivery

Antibiotic prophylaxis can never be a substitute for good surgical technique and meticulous asepsis. Despite this, controlled trials have shown, quite unequivocally, that a policy of routine antibiotic prophylaxis is associated with a threefold reduction in the risk of serious postoperative infection, localized wound infection, and endometritis, as well as the much commoner risk of postoperative fever, in women undergoing caesarean delivery. Furthermore, the magnitude of the benefit seems as great for elective section as it is for section after the onset of labour. Analyses also show that, except in units with a quite exceptionally low postoperative infection rate, such a policy reduces healthcare costs.

The cephalosporins and broad-spectrum penicillins (usually ampicillin) seem to be equally effective. The use of an aminoglycoside or metronidazole as well as a broad-spectrum penicillin and the duration of prophylaxis both deserve further study. One day of prophylaxis (starting, if necessary, after the umbilical cord has been cut) provides substantial protection. Continued treatment for several days, or the routine use of two antibiotics, have been shown to further reduce the risk of peri-operative infection, but this could have a detrimental effect on the bacterial ecology of the unit and increase the risk of infection from multi-resistant organisms.

Maternal prophylaxis

Mothers offered prophylaxis at caesarean delivery usually receive four doses of 2 g either intravenously or deep intramuscular injection at six-hourly intervals. It is not unreasonable to delay the first dose until the umbilical cord has been clamped.

Neonatal treatment

Babies were given 40 mg/kg intravenously once every 12 hours in the first week of life, once every eight hours when one to three weeks old, and once every six hours in babies older than this. The dose interval should be doubled when renal function is seriously impaired

Supply and administration

Cefoxitin was available in 1 and 2 gram vials in North America (costing approximately £5 and £10 each), but no company is currently marketing this antibiotic in the United Kingdom or Europe. For intravenous administration, powder from a 1 gram vial was mixed with 9.5 mL of water for injections to give a solution containing 100 mg/mL.

For intramuscular administration the contents of the 1 gram vial were dissolved with 2 ml of plain 1% lidocaine hydrochloride (lignocaine hydrochloride = former BAN). Intramuscular treatment was not recommended in small babies). Separate injection sites were used when giving adults the standard 2 g dose in two divided injections.


Goldin AB, Sawin RS, Garrison MM, et al. Aminoglycoside-based triple-antibiotic therapy versus monotherapy for children with ruptured appendicitis. Pediatrics 2007;119:905–11.Find this resource:

Mugford M, Kingston J, Chalmers I. Reducing the incidence of infection after Caesarean section: implications of prophylaxis with antibiotics for hospital resources. Brit Med J 1989;299:1003–6.Find this resource:

Regazzi MBG, Chirico G, Cristiani D, et al. Cefoxitin in newborn infants. Eur J Clin Pharmacol 1983;25:507–9.Find this resource:

Roos R, von Hattingberg HM, Belohradsky BH, et al. Pharmacokinetics of cefoxitin in premature und newborn infants studied by continuous serum level monitoring during combination therapy with penicillin and amikacin. Infection 1980;8:301–6.Find this resource:



Cimetidine inhibits gastric acid secretion. Ranitidine (q.v.) is a closely related drug with fewer side effects and fewer drug interactions.


Cimetidine is a relatively safe and once widely used drug, a low dose of which is now available ‘over the counter’ without prescription for the short-term management of indigestion and heartburn in adults. The drug, first synthesized in 1972, was designed to work by blocking the H2 histamine receptors in the stomach controlling the release of gastric acid, thereby also reducing pepsin output. High-dose treatment has been shown to speed the healing of peptic ulcers in the oesophagus, stomach, and duodenum, and low-dose maintenance treatment can be used to prevent a recurrence in vulnerable subjects. Omeprazole (q.v.) or other proton pump inhibitors may work when cimetidine or ranitidine do not.

Cimetidine and ranitidine have also been widely used to treat acute non-specific gastrointestinal bleeding, especially in patients undergoing intensive care (where acute haematemesis is often seen to be a sign of stress ulceration), but such haemorrhage often stops rapidly without specific treatment, and the 27 trials that have been done in adult patients failed to show clear evidence of benefit. Only one small trial has yet been attempted in the neonatal period.

Cimetidine is rapidly absorbed when taken by mouth and mostly excreted unchanged in the urine. The plasma elimination half-life is about two hours in adults, but rather more than this in the neonatal period. Side effects are rare, although dizziness, somnolence, and fatigue have been reported. Arrhythmia has been seen both in adults and in neonates, especially with rapid intravenous administration. Cimetidine has mild, dose-related, anti-androgenic properties, and reversible gynaecomastia has been reported. Ranitidine came to be used in preference to cimetidine by the mid-1990s in young children.

Cimetidine has an immunomodulatory action on T cells and use of this property is sometimes made to treat diffuse mastocytosis. It has also been used, with variable effect as a systemic treatment for cutaneous (including ano-genital) warts and when the poxvirus starts to cause disfiguring molluscum contagiosum.

Fetal and infant implications of maternal treatment

Cimetidine crosses the placenta and should be used with caution in early pregnancy, although teratogenicity has not been reported. It has been widely used in mothers during delivery without adverse effects being noted in the baby after delivery.

Use during lactation will result in the baby receiving (on a weight-for-weight basis) a dose equivalent to 5–7% of the maternal dose, but this does not seem to have caused problems. The interactions of cimetidine with other medications may sometimes preclude its use. There is not enough experience with its use for the manufacturers to recommend the use of this drug in children less than one year old.

Drug interactions

Cimetidine (unlike ranitidine) inhibits a number of cytochrome P450 enzymes (including CYP1A2, CYP2C9, CYP2D6 and CYP3A3/A4, and CYP2C18) and interferes with the breakdown of a number of drugs. Erythromycin, lignocaine, midazolam, nifedipine, phenytoin, suxamethonium, theophylline (or aminophylline), and warfarin are amongst the drugs most notably affected.


Give 5 mg/kg by mouth every six hours if there is evidence of active ulceration. Half this dose may be adequate when the drug is given prophylactically. Treatment can be given intravenously when necessary, but must be given slowly over at least ten minutes, and treatment with ranitidine (q.v.) is now generally preferred. Dosage must be halved or treatment stopped when there is renal or liver failure.

Supply and administration

An oral syrup containing 40 mg/mL of cimetidine (and 10% propylene glycol) is available from the pharmacy (300 ml costs £14). It contains methyl- and propyl- parahydroxybenzoates, propylene glycol, and sorbitol. In addition, each 5 mL of this syrup contains 12.8 mg of sodium.

In North America 2 mL ampoules for either intravenous or intramuscular use are available and these contain 300 mg of cimetidine. This parenteral preparation is longer readily available in the United Kingdom. If used intravenously the preparation must be diluted at least fivefold, and is most conveniently diluted tenfold, before use. 1 one mL of cimetidine from the ampoule and dilute to 15 mL with 0.9% sodium chloride to provide a preparation containing 10 mg/mL. Rapid intravenous administration can cause an arrhythmia.


Collins R, Langman M. Treatment with histamine H2 antagonists in acute upper gastrointestinal hemorrhage: implications of randomised trials. N Engl J Med 1985;313:660–76. [RCT]Find this resource:

Cotton RB, Hazinski TA, Morrow JD, et al. Cimetidine does not prevent lung injury in newborn premature infants. Pediatr Res 2006;59:795–800. [RCT]Find this resource:

Garbis H, Elefant E, Diav CO, et al. Pregnancy outcome after exposure to ranitidine and other H2-blockers. A collaborative study of the European Network of Teratology Information Services. Reprod Toxicol 2005;19:453–8.Find this resource:

Hohil M, Prendiville JS. Treatment of molluscum contagiosum with oral cimetidine in 13 children. Pediatr Dermatol 1996;13:310–12.Find this resource:

Lambert J, Mabassaleh M, Grand RJ. Efficacy of cimetidine for gastric acid suppression in pediatric patients. J Pediatr 1992;120:474–8.Find this resource:

Lloyd CW, Martin WJ, Taylor BD, et al. Pharmacokinetics and pharmacodynamics of cimetidine and metabolites in critically ill children. J Pediat 1985;107:295–300.Find this resource:

Ruigómez A, García Rodríguez LA, Cattaruzzi C, et al. Use of cimetidine, omeprazole, and ranitidine in pregnant women and pregnancy outcomes. Am J Epidemiol 1999;150:476–81.Find this resource:

Simonart T, de Maertelaer V. Systemic treatments for cutaneous warts: a systematic review. J Dermatolog Treat 2012;23:72–7. [SR]Find this resource:

Somogyi A, Gugler R. Cimetidine excretion into breast milk. Br J Clin Pharmacol 1979;7:627–9.Find this resource:

Vandenplas Y, Sacre L. The use of cimetidine in newborns. Am J Perinatol 1987;4:131–3.Find this resource:

Yashar SS, Shamiri B. Oral cimetidine treatment of molluscum contagiosum. Pediatr Dermatol 1999;16:493.Find this resource:

Ziemniak JA, Wynn RJ, Aranda JV, et al. The pharmacokinetics and metabolism of cimetidine in the premature newborn. Dev Pharmacol Ther 1984;7:30–8.Find this resource:

See also the relevant Cochrane review of use in molluscum contagiosum

van der Wouden JC, van der Sande R, Kruithof EJ, Sollie A, van Suijlekom-Smit LW, Koning S. Interventions for cutaneous molluscum contagiosum. Cochrane Database Syst Rev 2017;5:CD004767. Available at : this resource:



Cisapride was once widely used to treat babies with gastro-oesophageal reflux, but it was withdrawn in in most countries in 2000 when it became clear that drug accumulation could cause serious arrhythmia.


Cisapride is a substituted benzamide first patented in 1983 that increases gut motility without stimulating gastric secretion, probably by increasing the release of acetylcholine within the nerve plexus of the gut wall. It is readily absorbed when taken by mouth and undergoes rapid first-pass metabolism in the liver and gut wall. The metabolites are then excreted in the urine and faeces (the adult plasma elimination half-life is seven to ten hours). Bioavailability is approximately halved when the drug is given rectally. The commonest sign of an overdose in adults is abdominal cramp and intestinal hurry, but headache, dizziness, tachycardia and convulsions have also been reported. More seriously, drug accumulation can prolong the QT interval and cause a potentially dangerous arrhythmia (especially if there is hypokalaemia or hypomagnesaemia).

Cisapride can increase the tone of the gastro-oesophageal sphincter, accelerate gastric emptying, and mitigate some of the symptoms of gastro-oesophageal reflux but, despite widespread use, there is no controlled trial evidence that it is of any value in the management of neonatal reflux, and little evidence that it is of very much use in older children either. Use of the drug in neonates became widespread in the mid-1990s before any pharmacokinetic studies were done in young children even though the manufacturer never sought a license to recommend use in children less than 12 years old. Indeed, cisapride was being used in 80% of all UK neonatal units by 1998, and some units were giving it to 40% of their preterm babies. Use in the United States was equally widespread. Use then declined, almost as abruptly as it had risen, once controlled trials were completed and an overview of those trials was published by the Cochrane Collaboration.

Cisapride, and erythromycin (q.v.), both normally cause a decrease in small and large bowel transit time, but neither seems to reduce the time it usually takes for most preterm babies to achieve full enteral feeding. Unfortunately, we will never know whether further study might have shown that cisapride could be useful in the management of babies with stubborn ileus, especially after surgery, as serious arrhythmias associated with its use led to the product’s abrupt withdrawal.

Fetal and infant implications of maternal treatment

Little was ever known about use in pregnancy. High doses might potentially be fetotoxic.The breastfed baby would only be exposed to less than 1% of the maternal dose on a weight-for-weight basis during lactation.

Drug interactions

Patients taking amiodarone, doxapram, erythromycin, spiramycin, or any of the systemic imidazole or triazole antifungal agents (such as fluconazole) should never be given cisapride: these all interfere with the metabolic inactivation of cisapride and can prolong the QT interval, causing ventricular arrhythmia.


By mouth:

It was usual to start treatment at a dose of 200 micrograms/kg given once every 8–12 hours. The maximum daily dose was 800 micrograms/kg a day.


In those babies with gastroschisis or malrotation 1 mg/kg, given once every 12 hours, has been shown to be of benefit in the treatment of severe postoperative ileus.

Monitoring for toxicity

ECG measurement of the QT and RR intervals should be used to watch for potential overtreatment, especially in the preterm baby. Use lead II for consistency. The corrected QT interval (QTc = QT/√RR) averaged over five to ten beats should not exceed 0.45, or rise by more than 10% on treatment.


The drug is no longer on general sale in either the United States or the United Kingdom for use in humans although some use in veterinary practice still continues in North America. Use in humans in India was banned in as late as 2011, however cisapride is still available in some countries.

Cisapride monohydrate suspension, when available, contained the equivalent of 1 mg/mL of anhydrous cisapride, plus sucrose and parabens. It could be given rectally when necessary. A more dilute suspension was stable for seven days.


Bourke B, Drumm B. Cochrane’s epitaph for cisapride in childhood gastro-oesophageal reflux. Arch Dis Child 2002;86:71–2.Find this resource:

Cools F, Benatar A, Bruneel E, et al. A comparison of the pharmacokinetics of two dosing regimens of cisapride and their effects on corrected QT interval in premature infants. Eur J Clin Pharmacol 2003;59:17–22.Find this resource:

Kohl M, Wuerdemann I, Clemen J, et al. Cisapride may improve feeding tolerance of preterm infants: a randomized placebo-controlled trial. Biol Neonate 2005;88:270–5. [RCT] (See also Commentary on pages 276–7.)Find this resource:

Lander A, Desai A. The risks and benefits of cisapride in premature neonates, infants and children. Arch Dis Child 1998;79:469–70.Find this resource:

Lander A, Redkar R, Nicholls G, et al. Cisapride reduces neonatal postoperative ileus: a randomised placebo controlled trial. Arch Dis Child Fetal Neonatal Ed 1997;77:F119–22. [RCT]Find this resource:

Semama DS, Bernardini S, Louf S, et al. Effects of cisapride on QTc interval in term neonates. Arch Dis Child Fetal Neonatal Ed 2001;84:F44–6Find this resource:

Tréluyer J-M, Rey M, Sonnier M, et al. Evidence of impaired cisapride metabolism in neonates. Br J Clin Pharmacol 2001;52:419–25.Find this resource:

Vandenplas Y, Belli DC, Benatar A, et al. The role of cisapride in the treatment of pediatric gastroesophageal reflux. J Pediatr Gastroenterol Nutr 1999;28:518–28. (A European Society of Pediatric Gastroenterology, Hepatology and Nutrition statement)Find this resource:

See also the relevant Cochrane reviews

Maclennan S, Augood C, Cash-Gibson L, et al. Cisapride treatment for gastro-oesophageal reflux in children. Cochrane Database Syst Rev 2010;4:CD002300. Available at: this resource:

Tighe M, Afzal NA, Bevan A, et al. Pharmacological treatment of children with gastro-oesophageal reflux. Cochrane Database Syst Rev 2014;11:CD008550. Available at: this resource:



Didanosine is always used in combination with other drugs. It is now uncommon for it to be used to treat HIV infection due to a number of potentially serious adverse effects.


Didanosine, developed in 1986, was the second antiretroviral drug to be licensed after zidovudine (q.v.). It is a nucleoside reverse transcriptase inhibitor (NRTI) with many of the same properties as lamivudine (q.v.), though the latter is better tolerated. Didanosine is quite rapidly hydrolysed and inactivated by stomach acid and, as a result, the drug usually comes co-formulated with an antacid. The drug’s bioavailability is also further reduced if it is taken with, or shortly after, food. Clearance is related to postnatal age, rising rapidly in the first week of life and then more slowly over the next three to four months.

Serious adverse effects include retinal depigmentation, optic neuritis, peripheral neuropathy, and pancreatitis—most of which are dose related and all of which can be difficult to detect in a young child. All the NRTI drugs have the potential to cause mitochondrial dysfunction which can variably present as liver damage with hepatomegaly, hepatic steatosis, and potentially life-threatening lactic acidosis.

Sustained use in combination with protease inhibitors such as nelfinavir or ritonavir (q.v.) can also cause a marked loss of subcutaneous facial and limb fat (lipoatrophy) and an increase in truncal and abdominal fat (lipohypertrophy).

Fetal and infant implications of maternal treatment

Didanosine crosses the placenta and fetal levels are estimated to be therapeutic. If used during pregnancy the risks to the fetus from vertical transmission of the virus are greater than from the medication itself. However, the combination of stavudine and didanosine should not be prescribed in pregnancy as the risks of maternal lactic acidosis seem to be greatest with this. There is also some evidence that the fetus may also be affected by NRTI induced mitochondrial dysfunction.

Breastfeeding is not recommended in HIV-infected women where formula is available to reduce the risk of neonatal transmission. In countries where formula is not readily available or safe, ongoing use during breastfeeding is used to reduce transmission. Nothing is known about excretion of didanosine into breast milk.

New information on optimum management becomes available so frequently that communication with a Paediatric HIV/Infectious Diseases Specialist is essential. The diagnosis and management must also be discussed with, and supervised by, someone with extensive experience of this condition.

Early postnatal prophylaxis


When it was used, the usual neonatal dose was 60 mg/m2 by mouth twice a day, increasing to 100 mg/m2 twice a day by three months old. This is equivalent to a dose of about 3 mg/kg by mouth twice a day in any baby less than three months old, and a dose of 4.5 mg/kg at three months. A lower dose should be used when there is renal impairment.

Combination treatment:

Babies who were also taking another antiviral drug were given 100 mg/m2 once a day.


Pancreatitis is an uncommon but dangerous complication that may be hard to diagnose in a young child. Even an asymptomatic rise in serum amylase or lipase levels merits at least the prompt suspension, if not a complete change, of treatment. Many authorities recommend retinal examination once every six months after prior dilatation of the pupils, especially in young children.


Didanosine can be supplied as 25 mg tablets combined with an antacid. These need to be chewed before being swallowed, but they can also be crushed and dispersed in water or apple juice. Didanosine is also usually available as a 10 mg/mL suspension, buffered in an antacid, on a ‘named patient’ basis which is stable for a month if kept at 4 °C.

No parenteral preparations are available.


Crain MJ, Chernoff MC, Oleske JM, et al. Possible mitochondrial dysfunction and its association with antiretroviral therapy use in children perinatally infected with HIV. J Infect Dis 2010;202:291–301.Find this resource:

Kovacs A, Cowles MK, Britto P, et al. Pharmacokinetics of didanosine and drug resistance mutations in infants exposed to zidovudine during gestation and postnatally and treated with didanosine or zidovudine in the first three months of life. Pediatr Infect Dis J 2005;24:503–9.Find this resource:

Lallemant M, Ngo-Giang-Huong N, Jourdain G, et al. Efficacy and safety of 1-month postpartum zidovudine-didanosine to prevent HIV-resistance mutations after intrapartum single-dose nevirapine. Clin Infect Dis 2010;50:898–908.Find this resource:

Mueller BU, Butler KM, Stocker VL, et al. Clinical and pharmacokinetic evaluation of long term therapy with didanosine in children with HIV infection. Pediatrics 1994;94:724–31.Find this resource:

Perry CM, Noble S. Didanosine. An updated review of its use in HIV infection. Drugs 1999;58:1099–135. [SR]Find this resource:

Rongkavilit C, van Heeswijk RP, Limpongsanurak S, et al. Pharmacokinetics of stavudine and didanosine coadministered with nelfinavir in human immunodeficiency virus-exposed neonates. Antimicrob Agents Chemother 2001;45:3583–90.Find this resource:

Taylor GP, Clayden P, Dhar J, et al. British HIV Association guidelines for the management of HIV infection in pregnant women 2012. HIV Med 2012;13 (Suppl 2):87–157.Find this resource:

Townsend CL, Willey BA, Cortina-Borja M, et al. Antiretroviral therapy and congenital abnormalities in infants born to HIV-infected women in the UK and Ireland, 1990-2007. AIDS 2009;23:519–24.Find this resource:



Intravenous enoximone is sometimes used in the short-term management of heart failure that fails to respond to other forms of treatment. The manufacturers have not yet endorsed the use of enoximone in infants or children. Milrinone (q.v.) is an easier drug to administer.


Enoximone, patented in 1980, is a selective (type 3) phosphodiesterase inhibitor acting mainly on the myocardium as an inotrope. It is also a mild vasodilator. Long-term oral use seems to be associated with an increase in mortality in adults with congestive failure, and the drug is now only used in the short-term intravenous management of patients in whom a low cardiac output persists despite treatment with a catecholamine such as dobutamine (q.v.).

Preoperative monitoring has certainly shown enoximone to be of short-term benefit in restoring myocardial function after bypass surgery. It seems to work by increasing the intracellular concentration of cyclic AMP, which might explain why the effectiveness appears to be enhanced by simultaneous catecholamine use to stimulate the cardiac β‎-receptors.

Enoximone is excreted in the urine but is also partially oxidized in the liver to a pharmacologically active, metabolite, enoximone sulfoxide (also excreted in urine). The half-life is much the same in infancy as it is in adult life but varies widely, particularly as many of the patients in whom it is used have hepatic and renal dysfunction due to their underlying disease state that requires treatment with this drug. The half-life is one to four hours in healthy volunteers and twice this in patients in heart failure. It is even longer where renal function is poor. The volume of distribution is also high (VD 3.6 L/kg), making it important to employ an initial loading dose. Use could be hazardous in patients with outlet obstruction or hypertrophic cardiomyopathy (as with any inotrope).

Fetal and infant implications of maternal treatment

There is no published evidence relating to the use of enoximone in pregnancy, and it is not known whether the drug is excreted into breast milk. There is no animal evidence of teratogenicity.


Give 500 micrograms/kg of enoximone over 15 minutes (infuse 0.2 mL for each kilogram the baby weighs of a solution made up as described under ‘Supply and administration’ below). Maintenance doses of between 5 and up to 20 micrograms/kg per minute are used, by infusing the same solution at the rates in Table B1.

Table B1 Dose

Dose (micrograms/kg/min)

Rate of infusion (ml/kg per hour)









Drug accumulation is a potential hazard in renal failure. The benefits seen at the start of treatment seem to wane with time. Treatment following corrective cardiac surgery is rarely continued for more than one or two days.

Supply and administration

Enoximone can be obtained in 20 mL ampoules containing 5 mg/mL. Dilute immediately before use with an equal volume of water for injection to obtain a solution containing 2.5 mg/mL and prepare a fresh solution once every 24 hours. These ampoules also contain propylene glycol and ethanol (see the section on excipients for further details on the dangers of these).

Enoximone should not be co-infused with any other drug. It is incompatible with glucose, and dilution with 0.9% sodium chloride imposes a relatively large obligatory sodium load on the baby. The manufacturers are not even prepared to say that it is safe to infuse enoximone through a terminal Y connector into a line containing glucose because solubility problems cause rapid crystal formation which can narrow, and occasionally block, an intravenous line even when the drug is infused in saline. Make sure that the solution is still a clear yellow colour prior to administration. Keep ampoules at below 20 ºC.


Booker PD, Gibbons S, Stewart JI, et al. Enoximone pharmacokinetics in infants. Br J Anaesth 2000;85:205–10.Find this resource:

Hausdorf G, Friedel N, Berdjis F, et al. Enoximone in newborns with refractory postoperative low-output states (LOS). Eur J Cardiothoracic Surg 1992;6:311–17.Find this resource:

Huggon I, James I, Macrae D. Hyperosmolality related to propylene glycol in an infant treated with enoximone infusion. Brit Med J 1990;301:19–20.Find this resource:

Innes PA, Frazer RS, Booker PE, et al. Comparison of the haemodynamic effects of dobutamine with enoximone after open heart surgery in small children. Br J Anaesth 1994;72:77–81.Find this resource:

Kirsten R, Nelson K, Kirsten D, et al. Clinical pharmacokinetics of vasodilators. Part II. Clin Pharmacokinet 1998;35:9–36.Find this resource:

Vernon MW, Heel RC, Brogden RN. Enoximone: a review of its pharmacological properties and therapeutic potential. Drugs 1991;42:997–1017.Find this resource:

Etamsylate = ethamsylate (former BAN)


Etamsylate was once widely used in the supposition that it would prevent intraventricular bleeding in babies of ≤ 32 weeks gestation and in doing so reduce long-term morbidity and mortality; sadly, it did not seem to achieve the longer-term, and more meaningful, aims.


Etamsylate (diethyl ammonium 2,5-dihydroxybenzene sulfonate) is a water-soluble non-steroidal drug, first discovered in 1959, that has been used for several decades to reduce capillary bleeding in adults during surgery and also to lessen the blood loss in menorrhagia.

Etamsylate is thought to work principally by maintaining capillary integrity, probably by promoting polymerization of mucopolysaccharide in vessel walls. It may also inhibit the action of prostacyclin in adrenaline-induced platelet aggregation. Following systemic administration, the mean bleeding time is significantly reduced without any effect on cell counts, fibrinolysis, prothrombin time, or clotting time. The drug is excreted unchanged, mainly in the urine. Adults sometimes experience nausea; transient headaches and skin rashes have also been reported on occasion.

A double-blind, placebo controlled, multicentre trial of early prophylactic treatment in babies of < 1500 g in the UK in 1986 was initially interpreted as showing that etamsylate can reduce the incidence of ultrasound-diagnosed intraventricular haemorrhage (IVH) by a third. However, such a clear-cut benefit could only be identified by excluding from analysis those children who died and those children who had evidence of haemorrhage when first examined shortly after birth.

A later European trial, completed in 1994, found no such benefit, but a recent overview of all available trial data does suggest that the total incidence of intraventricular bleeding is reduced. Unfortunately, the long-term follow-up of the children from these two trials shows that this does not translate into any reduction in the number who died or who only survive with significant disability. More recent work suggested that etamsylate modifies prostaglandin biosynthesis, and this may help to explain the apparent reduction in symptomatic patent ductus arteriosus in etamsylate-treated babies in the UK trial.

Fetal and infant implications of maternal treatment

There are no real indications to use this drug during pregnancy, thus experience is limited. It is known to cross the placenta but there is no evidence of teratogenicity in animal studies.

Etamsylate passes into breast milk but is not known to be harmful to the breastfed infant, nonetheless the manufacturers advise against its use in the breastfeeding mother.

Strategies for preventing IVH

Other strategies that have been tried include giving phenobarbital or vitamin K before birth or fresh frozen plasma, ibuprofen, indometacin, phenobarbital, or vitamin E (q.v.) after birth. Even prophylactic ibuprofen and indometacin, the most successful strategies studied to date, have not been shown to improve long-term outcome convincingly as yet, even though they do reduce the number of babies developing ultrasound evidence of serious periventricular bleeding. Many of the early trials were launched before it became clear that long-term disability is seldom seen in survivors unless there has been parenchymal haemorrhage (haemorrhage into the brain substance) or post-haemorrhagic hydrocephalus as well as intraventricular or subependymal bleeding.

More recently it has become clear that ischaemia, rather than bleeding, causes much of the perinatal brain damage seen in babies of ≤ 32 weeks gestation. Whether measures of total cerebral perfusion (as documented by measuring superior vena caval blood flow) are a useful marker of this remains unclear. Blood flow, rather than blood pressure, would seem to be what counts, but flow (unfortunately) cannot be measured as easily as pressure. Changes in vascular tone may influence local tissue perfusion even when total cardiac output and gross regional perfusion seems to be more than adequate (and hypocapnia and hyperoxia both have a major influence on cerebral vascular tone).


For some time, many units would prophylactically give ‘at risk’ babies 12.5 mg/kg of etamsylate either intravenously or intramuscularly within one hour of birth, and further intravenous doses every six hours for four days (i.e. a total of 200 mg/kg over four days).


Etamsylate is no longer available in the United Kingdom, 2 mL ampoules containing 250 mg of etamsylate could be imported by pharmacies on special request. For oral use 500 mg tablets were once fairly widely used in the treatment of menorrhagia.


Benson JWT, Drayton MR, Hayward C, et al. Multicentre trial of ethamsylate for prevention of periventricular haemorrhage in very low birthweight infants. Lancet 1986;ii:1297–300 (see also Lancet 1987;i:623–4). [RCT]Find this resource:

Elbourne E, Ayers S, Dellagrammaticas H, et al. Randomised controlled trial of prophylactic etamsylate: follow up at 2 years of age. Arch Dis Child Fetal Neonatal Ed 2001;84:F183–7. [RCT]Find this resource:

Sanghvi KP, Merchant RH, Karnik A, et al. Role of ethamsylate in preventing periventricular-intraventricular hemorrhage in premature infants below 34 weeks of gestation. Indian Pediatr 1999;36:653–8. [RCT]Find this resource:

Schulte J, Osborne J, Benson JWT, et al. Developmental outcome of the use of etamyslate for prevention of periventricular haemorrhage in a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed 2005;90:F31–5. [RCT] (See also F3–5.)Find this resource:

The EC Ethamsylate Trial Group. The EC randomised controlled trial of prophylactic ethamsylate for very preterm neonates: early mortality and morbidity. Arch Dis Child Fetal Neonatal Ed 1994; 70: F201–5. [RCT]Find this resource:

See also the relevant Cochrane reviews

Hunt R, Hey E. Ethamsylate for the prevention of morbidity and mortality in preterm or very low birth weight infants. Cochrane Database Syst Rev 2010;B1:CD004343. Available at: this resource:

Shepherd E, Salam RA, Middleton P, et al. Neonatal interventions for preventing cerebral palsy: an overview of Cochrane Systematic Reviews. Cochrane Database Syst Rev 2018;6:CD012409. Available at: this resource:

Indometacin = Indomethacin (USAN and former BAN)


Indometacin causes effective patent ductus arteriosus (PDA) closure. The absence of a readily available supply means ibuprofen and paracetamol (q.v.) have now become the main medical treatments for clinically significant PDA. In many countries, however, there is an increasing trend toward conservative management of patients diagnosed with PDA and that the short-term benefits of treatment do not necessarily translate into longer-term ones.


Indometacin is a non-selective inhibitor of cyclo-oxygenase (COX) 1 and 2, the enzymes that participate in prostaglandin synthesis from arachidonic acid. It is widely used as an analgesic anti-inflammatory in rheumatoid arthritis and gout. It is normally well absorbed by mouth, but neonatal oral absorption can be unpredictable. The neonatal half-life averages 16 hours (nearly seven times the half-life in adults).

Indometacin was first used experimentally to effect ductal closure in 1976, and some centres still use the dose used in the early studies (three 200 microgram/kg doses 12 hours apart). This dose is of proven value in the treatment of symptomatic patent ductus, especially when used within two weeks of birth, but more sustained treatment is measurably more effective in the very preterm baby (where the risk of treatment failure is highest), as is the use of a higher dose.

A left atrium to aortic root (LA:Ao) ratio of 1.5 or more, a ductal diameter on colour Doppler of over 1.3 mm/kg, and descending aortic flow reversal in diastole on ultrasound after the first two days of life, all suggest the presence of a haemodynamically significant duct. Babies offered early prophylaxis (as in the TIPP trial) had less ultrasound evidence of serious intraventricular haemorrhage, but cerebral palsy and other disability was no less common. Nor was bronchopulmonary dysplasia (BPD) less common. However, for every 20 babies of < 1 kg treated, five avoided prolonged duct patency and one avoided duct ligation. Evaluation at school entry has failed to confirm an earlier report that early prophylaxis reduces the number of survivors with speech and language problems. Nor, however, is there any evidence that early low-dose use increases the risk of necrotizing enterocolitis or ischaemic brain damage—an issue of real concern since even slow infusion causes a brief drop in cerebral, renal, and gut blood flow.

Serious coagulation problems are traditionally considered a contraindication to neonatal treatment because of the effect of indometacin on platelet function, as is necrotizing enterocolitis. Jaundice is not a contraindication. The decrease in urine flow is transient even with sustained treatment, so indometacin can still be given, even when there are early signs of renal failure, and no adjustment needs to be made in the dosage of other renally excreted drugs. Focal ischaemic gut perforation is the most dangerous, and gastrointestinal haemorrhage the commonest, complication (even with intravenous administration). Whether sustained, or high-dose, treatment increases the risk of these complications is not yet clear. Ligation is only justified if the duct remains symptomatic as well as patent, since there are suggestions that ligation may occasionally make any existing BPD worse.

Fetal and infant implications of maternal treatment

Indometacin crosses the placenta and is excreted in fetal urine. There is no evidence of teratogenicity. Maternal treatment (25 mg by mouth every 6 hours after a loading dose of 50 mg) was sometimes used to treat polyhydramnios, but use (in higher doses) to control premature labour has now declined because there are better alternatives. Some recent studies have also suggested such use may also increase the risk of the baby developing necrotizing enterocolitis, and focal gut perforation. A recent meta-analysis did not find any increase in the risk of treatment-resistant PDA, but it did find that periventricular leukomalacia was more common.

Breastfeeding is quite safe because the baby gets less than 1% of the weight-adjusted maternal dose.

Drug interactions

Babies given steroids while on indometacin are at increased risk of focal ischaemic gut perforation.


Early pre-emptive treatment:

Babies with a gestational age < 28 weeks were given three daily doses of 100 microgram/kg of indometacin. These were given by slow intravenous infusion over 20 minutes starting 12 hours after birth (as in the TIPP trial).

Haemodynamically significant ducts:

A commonly used regime involved administration of a single dose of 200 microgram/kg (by slow intravenous infusion over 20 minutes), and then doses of 100 microgram/kg, 24 and 48 hours later. A further three days of treatment was sometimes used if this did not close the duct in very preterm babies with residual patency and halved the number eventually judged to need surgical ligation. A higher dose of indomethacin was no more effective and seems to exacerbate any co-existent retinopathy of prematurity.


The UK preparation of indometacin for intravenous use (Indocid®) is no longer manufactured.

Limited supplies, of a North American product of lyophilized indometacin (1 mg per vial) were for a time obtained through specialist importing companies, however whether this will continue to be available is unclear for a number of reasons (the company that produced this preparation also manufactures the North American preparation of ibuprofen for the same indication).


Ami SB, Sinkin RA, Glantz JC. Metaanalysis of the effect of antenatal indomethacin on neonatal outcomes. Am J Obstet Gynecol 2007;197:486.e1–496.e10. [SR]Find this resource:

Clyman R, Cassady G, Kirklin JK, et al. The role of patent ductus arteriosus ligation in bronchopulmonary dysplasia: reexamining a randomized controlled trial. J Pediatr 2009;154:873–6. [RCT]Find this resource:

Friedman WF, Hirschklau MJ, Printz MP, et al. Pharmacologic closure of patent ductus arteriosus in the premature infant. N Engl J Med 1976;295:526–9.Find this resource:

Jegatheesan P, Ianus V, Buchh B, et al. Increased indomethacin dosing for persistent patent ductus arteriosus in preterm infants: a multi-center, randomized, controlled trial. J Pediatr 2008;153:1839. [RCT]Find this resource:

Kabra NS, Schmidt B, Roberts RS, et al. Neurosensory impairment after surgical closure of patent ductus arteriosus in extremely low birth weight infants: results from the trial of indomethacin prophylaxis in preterms. J Pediatr 2007;150:229–34 (see also 216–19).Find this resource:

Ngo S, Profit J, Gould JB, Lee HC. Trends in patent ductus arteriosus diagnosis and management for very low birth weight infants. Pediatrics 2017;139. e20162390.Find this resource:

Smith CL, Kissack CM. Patent ductus arteriosus: time to grasp the nettle? Arch Dis Child Fetal Neonatal Ed 2013;98:F269–71.Find this resource:

Sperandio M, Beedgen B, Feneberg R, et al. Effectiveness and side effects of an escalating, stepwise approach to indomethacin treatment of symptomatic patent ductus arteriosus in premature infants below 33 weeks gestation. Pediatrics 2005;116:1361–6 (see also 117:1863–4).Find this resource:

See also the relevant Cochrane reviews

Cooke L, Steer P, Woodgate P. Indomethacin for asymptomatic patent ductus arteriosus in preterm infants. Cochrane Database Syst Rev 2003;2:CD003745. Available at: this resource:

Fowlie PW, Davis PG, McGuire W. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database Syst Rev 2010;7:CD000174. Available at: this resource:

Görk AS, Ehrenkranz RA, Bracken MB. Continuous infusion versus intermittent bolus doses of indomethacin for patent ductus arteriosus closure in symptomatic preterm infants. Cochrane Database Syst Rev 2008;1:CD006071. Available at: this resource:

Herrera C, Holberton J, Davis P. Prolonged versus short course of indomethacin for the treatment of patent ductus arteriosus in preterm infants. Cochrane Database Syst Rev 2007;2:CD003480. Available at: this resource:

Malviya MN, Ohlsson A, Shah SS. Surgical versus medical treatment with cyclooxygenase inhibitors for symptomatic patent ductus arteriosus in preterm infants. Cochrane Database Syst Rev 2013;3:CD003951. Available at: this resource:



Inositol perhaps deserves further investigation as a prophylactic nutritional supplement that can be used to reduce the severity of respiratory distress due to surfactant deficiency; whether it retains its early promise as a therapeutic agent in the era of high rates of antenatal steroids and exogenous surfactants is unclear.

Early evidence that it may reduce the severity of retinopathy of prematurity (ROP) seems not to have been borne out in a recent trial.

Nutritional factors

Inositol exists in nine possible stereoisomers, of which the most prominent form is myo-inositol. It is a six carbon sugar alcohol, at least as abundant as glucose in the body and is a precursor of various cell-membrane phospholipids. High levels potentiate the glucocorticoid induced acceleration of lung surfactant production by bringing about the maturation of the surfactant phospholipids, phosphatidylcholine and phosphatidylinositol.

Breast milk and colostrum, especially when delivery is preterm, are rich in inositol; however, artificial milk contains much less. The fluids used to provide parenteral nutrition are totally deficient. Serum concentrations are high during fetal life, and later fall. Neonatal inositol levels rise when there is anuria, presumably because of reduced catabolism or excretion. There have been reports suggesting that some folate-resistant neural tube defects may be prevented by inositol supplementation.

Serum levels of inositol rise after birth in babies fed breast milk, whereas in infants receiving parenteral nutrition they tend to fall. Inositol is well absorbed by mouth but can also be given intravenously. Two Finnish controlled trials involving 295 babies in the 1980s suggested that ventilator-dependent babies of less than 2 kg offered oral or intravenous inositol supplementation required less ventilation, had fewer pneumothoraces, and were less likely to develop chronic lung disease than placebo matched controls. Mortality is also reduced. In one trial there was also a reduced incidence of severe retinopathy of prematurity.

The 2015 Cochrane meta-analysis suggested that inositol could reduce the numbers of babies who developed significant (i.e. stage 3 or worse) ROP. On the back of this a large multicentre trial of use in infants born before 28 weeks was undertaken. This was terminated before reaching its pre-planned sample size due to a combination of a manufacturing issue and the outcome of a pre-planned safety review. This Data and Safety Monitoring Committee review that found a statistically significant increase in all-cause deaths through 55 weeks’ postmenstrual age in the myo-inositol group which was felt to be unrelated to the manufacturing issue.


In the larger of the two early trials alluded to earlier, babies were given 80 mg/kg of inositol intravenously over five minutes twice a day for five days. In the earlier trial the healthier babies were given inositol by mouth. Treatment was suspended if there was anuria or evidence of renal failure. A second course was given after two weeks in those babies who were still largely parenterally fed.

The most recent RCT of myo-inositol used a dose of 40 mg/kg every 12 hours (based on earlier pharmacokinetic studies by the same group). This was given intravenously initially and was then switched to enteral when the baby was almost fully enterally fed.


No commercial preparation is currently available but material suitable for oral use could be obtained by the local pharmacy on request—this is likely to be regarded as a nutritional supplement rather than a drug, and a sterile preparation suitable for intravenous use could be prepared on request. There is nothing to stop its use on a ‘named patient’ basis (as with other unlicensed drugs) but its use in the context of a clinical trial would require the prior issue of a Clinical Trials Authorisation (CTA) by the Medicines and Healthcare products Regulatory Agency and appropriate ethical approval.


Carver JD, Stromquist CI, Benford VJ, et al. Postnatal inositol levels in preterm infants. J Perinatol 1997;17:389–92.Find this resource:

Cavalli P, Tonni G, Grosso E, et al. Effects of inositol supplementation in a cohort of mothers at risk of producing an NTD pregnancy. Birth Defects Res A Clin Mol Teratol 2011;91:962–5.Find this resource:

Friedman CA, McVey J, Borne MJ, et al. Relationship between serum inositol concentration and development of retinopathy of prematurity: a prospective study. J Pediatr Ophthalmol Strabismus. 2000;37:79–86. [RCT]Find this resource:

Hallman M, Arjomaa P, Hoppu K. Inositol supplementation in respiratory distress syndrome: relationship between serum concentration, renal excretion, and lung effluent phospholipids. J Pediatr 1987;110:604–10.Find this resource:

Hallman M, Bry K, Hopper K, et al. Inositol supplementation in premature infants with respiratory distress syndrome. N Engl J Med 1992;326:1233–9. [RCT]Find this resource:

Hallman M, Järvepää A-L, Pohjavouri M. Respiratory distress syndrome and inositol supplementation in preterm infants. Arch Dis Child 1986;61:1076–83. [RCT]Find this resource:

Hallman M, Pohjavuori M, Bry K. Inositol supplementation in respiratory distress syndrome. Lung 1990;168 (Suppl):877–82.Find this resource:

Hylander MA, Strobino DM, Pezzullo JC, et al. Association of human milk feedings with a reduction in retinopathy of prematurity among very low birthweight infants. J Perinatol 2001;21:356–62.Find this resource:

Phelps DL, Ward RM, Williams RL, et al. Pharmacokinetics and safety of a single intravenous dose of myo-inositol in preterm infants of 23-29 wk. Pediatr Res 2013;74:721–9.Find this resource:

Phelps DL, Ward RM, Williams RL, et al. Safety and pharmacokinetics of multiple dose myo-inositol in preterm infants. Pediatr Res 2016;80:209–17.Find this resource:

Phelps DL, Watterberg KL, Nolen TL, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Effects of myo-inositol on type 1 retinopathy of prematurity among preterm infants <28 weeks' gestational age: a randomized clinical trial. JAMA 2018;320:1649–58. [RCT]Find this resource:

See also the relevant Cochrane reviews

Howlett A, Ohlsson A, Plakkal N. Inositol in preterm infants at risk for or having respiratory distress syndrome. Cochrane Database Syst Rev 2015;2:CD000366. Available at: this resource:

Interferon alfa


Interferon alfa was previously used to induce the early regression of life-threatening corticosteroid-resistant haemangiomas of infancy. However, it is no longer recommended due to the high incidence of spastic diplegia associated with its use and the availability of alternative treatments such as prednisolone and propranolol (q.v.).

Combined treatment with ribavirin (q.v.) can control hepatitis B and C infection in older children and adults (although tenofovir is the primary antiviral drug used in hepatitis B infection during pregnancy).

Vascular birth marks

Haemangiomas are common in infancy. Seldom noticed at birth, they grow rapidly for six to nine months and then gradually involute during early childhood. Bleeding is uncommon. Usually solitary and superficial, they are most often found on the head and neck. They are particularly common in preterm babies and occur in almost a quarter of babies of less than 28 weeks gestation. Superficial dermal haemangiomas are fleshy and bright red (‘strawberry naevi’), but deeper ones only show surface telangiectasia or a bluish hue. Lesions around the eye can cause amblyopia and sub-laryngeal lesions can cause serious bi-directional stridor as they grow. Children with multiple lesions sometimes have visceral haemangiomas. Large lesions can cause thrombocytopenia from platelet trapping (the Kasabach–Merritt syndrome) and high-output heart failure.

Treatment is mainly reserved for those lesions causing airway or visual obstruction, facial distortion, or thrombocytopenia. Propranolol has now largely supplanted steroids as the treatment of choice and has the advantage that it also works in haemangioma that are resistant to steroids. Systemic (and, on occasion, intra-lesional) corticosteroids were the mainstay of pharmacologic management of infantile haemangiomas since the 1960s whilst vincristine has been used for extensive haemangiomatosis not responsive to other treatments. Pulsed-dye laser treatment can render port-wine stains less noticeable, but is little used in the treatment of haemangiomas.

Other vascular malformations, in contrast, do not generally increase in size disproportionately after birth. Although by definition congenital, they may not be noticed for some months. Capillary and venous malformations lose their colour on compression (unlike strawberry naevi). Most capillary malformations (‘port-wine stains’) are flat and sharply demarcated. The paler salmon-coloured patches, often seen on the forehead, nose, and eyelids always fade with time, although patches on the nape of the neck (‘stork bites’) sometimes persist. Lymphatic and mixed malformations are usually noticed within a few months of birth. Venous and arteriovenous lesions are seldom suspected at birth.


Interferons are proteins or glycoproteins produced by the body in response to viral and other stimuli. Interferon alfa is derived from leukocytes, interferon beta from fibroblasts, and interferon gamma from stimulated T-lymphocytes. Human alfa interferon was first manufactured artificially from bacteria in 1980 using recombinant DNA technology (as indicated by the use of the suffix ‘rbe’). It has since been used to treat chronic hepatitis B and C, and certain types of leukaemia, myeloma, and lymphoma. Flu-like symptoms and fever are the only common problems, but nausea, lethargy, and depression can occur with high-dose treatment. Motor problems have been seen with use in young children, but these usually seem to resolve when treatment is stopped.

The fact that interferon alfa is of benefit in the management of Kaposi sarcoma, an endothelial cell tumour associated with HIV infection, has led to its use to suppress the endothelial proliferation that forms the cellular basis of other haemangiomatous lesions. It is also used in the treatment of a number of haematogenous malignancies and myeloproliferative disorders in adults.

Fetal and infant implications of maternal treatment

Little is known about use during pregnancy, but it does not seem to pose a toxic or teratogenic threat in a number of case reports. Animal studies have, however, shown some toxicity. Only small amounts appear in breast milk.


Serious haemangiomatous lesions that fail to respond to other treatments are sometimes treated with interferon alfa-2a. The usual dose is 3 million units/m2 subcutaneously once a day (i.e. 600,000 units for an average baby of 3 kg). Use should be reserved for a life-threatening situation.


A range of products are available, but there is no convenient low-dose preparation suitable for neonatal use. Of the available options, the best seem to be:

  • a multidose pre-filled pen containing 18 million units in 1.2 mL of interferon alfa-2b (rbe) (Intron-A®). This delivers six 0.2 mL doses each containing 3 million units (at a cost of £21 per dose).

  • a 10 million unit vial containing powder of the same interferon alfa-2b (rbe) requiring reconstitution with water (as supplied). When reconstituted this provides 10 million units per mL (10 mega units per mL).

The alternative product, interferon alfa-2a (rbe) (Roferon-A®), is best avoided when treating babies because it contains benzyl alcohol as an excipient. The products should be stored at 4 ºC, but not frozen.

Polyethylene glycol-conjugated or ‘pegylated’ derivatives of interferon alfa (peginterferon alfa-2a and peginterferon alfa-2b) are also available but are used in older children and adults. Pegylation increases the circulating half-life of the interferon and means that fewer or less frequent treatments may be needed.


Barlow CF, Priebe CJ, Mulliken JB, et al. Spastic diplegia as a complication of Interferon alfa-2a treatment of hemangiomas of infancy. J Pediatrics 1998;132:527–30.Find this resource:

Batta K, Goodyear HM, Moss C, et al. Randomised controlled trial of early pulsed dye laser treatment of uncomplicated childhood haemangiomas: results of a 1-year analysis. Lancet 2002;360:521–7 (see also 361:348–9). [RCT]Find this resource:

Chang LC, Haggstrom AN, Drolet BA, et al. Growth characteristics of infantile hemangiomas: implications for management. Pediatrics 2008;122:360–7.Find this resource:

Davison SM, Kelly DA. Management strategies for hepatitis C virus infection in children. Paediatr Drugs 2008;10:357–65.Find this resource:

European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol 2017;67:370–98.Find this resource:

Gruinwald JH, Burke DK, Bonthius DJ, et al. An update on the treatment of haemangiomas in children with interferon alfa-2. Arch Otolaryngol Head Neck Surg 1999;125:21–7.Find this resource:

Lee KC, Bercovitch L. Update on infantile hemangiomas. Semin Perinatol 2013;37:49–58.Find this resource:

Pope E, Krafchik BR, Macarthur C, et al. Oral versus high-dose corticosteroids for problematic hemangiomas: a randomized, controlled trial. Pediatrics 2007;119:e1239–47. [RCT]Find this resource:

Sakai K, Ueda A, Hasegawa M, Ueda Y. Efficacy and safety of interferon alpha for essential thrombocythemia during pregnancy: two cases and a literature review. Int J Hematol 2018;108:203–7.Find this resource:

Sans V, de la Roque ED, Berge J, et al. Propranolol for severe infantile hemangiomas: follow-up report. Pediatrics 2009;124:e423–31.Find this resource:

See also the relevant Cochrane review

Hauser G, Awad T, Brok J, et al. Peginterferon plus ribavirin versus interferon plus ribavirin for chronic hepatitis C. Cochrane Database Syst Rev 2014;2:CD005441. Available at: this resource:

Isoprenaline = Isoproterenol (USAN)


Isoprenaline is a sympathomimetic drug sometimes used in the management of haemodynamically significant bradycardia or heart block. It has also been used to control torsades de pointes when it complicates congenital long QT syndrome.


Isoprenaline is a synthetic sympathomimetic related to noradrenaline (q.v.) with potent β‎1- and β‎2-adrenergic receptor activity that was first brought into clinical use in 1951. It has virtually no effect on α‎-adrenergic receptors. Gastrointestinal absorption is unpredictable but sublingual administration is effective and the drug was widely given by aerosol as a bronchodilator for asthma in the 1960s before it was superseded by more selective β‎2-adrenergic agonists like salbutamol.

Isoprenaline is 50% excreted unchanged in the urine and also metabolised by catechol-O-methyl transferase in the liver, lungs, and tissues. Isoprenaline has a plasma half-life of two to three minutes in adults but this is slightly longer in children (4.2 +/– 1.5 minutes).

Continuous intravenous infusion can cause marked vasodilatation and a significant increase in cardiac output, an effect further potentiated by the drug’s inotropic and chronotropic action, and by an increase in cardiac venous return. It has more effect on heart rate than on stroke volume, and has relatively little effect on renal blood flow. Isoprenaline is known to be of value in the management of low cardiac output with or without pulmonary hypertension in older children and adults. It is probably under-utilized in the neonatal period. While a high dose can cause hypotension this is usually transient. There is also some risk of tachycardia and cardiac arrhythmia, but these toxic effects usually subside very rapidly as soon as treatment is stopped.

Treatment with isoprenaline is still sometimes appropriate in the initial management of complete atrioventricular (AV) heart block until such time as a permanent pacemaker can be implanted.

Fetal and infant implications of maternal treatment

There is no evidence that maternal use causes fetal malformations or adverse neonatal outcomes and, although isoprenaline does cross the placenta, it does not correct any fetal bradycardia. There is no reported experience with this drug during lactation.


Treatment was initiated using a continuous intravenous infusion at a rate of 20 nanogram/kg per minute (0.2 mL/hour of a solution made up as described under ‘supply and administration’ following). The rate was increased as necessary to a maximum of 200 nanogram/kg per minute (2 mL/hour of the standard dilution).


Isoprenaline can be added (terminally) into a line containing standard total parenteral nutrition (TPN) (with or without lipid) when absolutely necessary, and into a line containing dobutamine, heparin, or milrinone. Isoprenaline is only stable in acid solutions, and should never, therefore, be infused into the same line as sodium bicarbonate.

Supply and administration

Isoprenaline is no longer available in the United Kingdom. If required, 2 mL ampoules containing 2 mg of isoprenaline could be obtained on special order. The ampoules must be protected from light prior to use. To give an infusion of 10 nanogram/kg per minute place 300 micrograms (0.3 mL) of isoprenaline for each kilogram the baby weighs in a syringe, dilute to 50 mL with 10% glucose or glucose and sodium chloride, and infuse at a rate of 0.1 mL/hour.

A less concentrated solution of glucose or glucose and sodium chloride can be used where necessary. The drug is relatively stable in solutions with a low pH such as glucose and does not need to be prepared afresh every 24 hours.


Driscoll DJ. Use of inotropic and chronotropic agents in neonates. Clin Perinatol 1987;14:931–49.Find this resource:

Drummond WH. Use of cardiotonic therapy in the management of infants with PPHN. Clin Perinatol 1984;11:715–28.Find this resource:

Fukushige J, Takahashi N, Ingasashi H, et al. Perinatal management of congenital complete atrioventricular block: report of nine cases. Acta Paediatr Jpn 1998;40:337–40.Find this resource:

Komarlu R, Beerman L, Freeman D, et al. Fetal and neonatal presentation of long QT syndrome. Pacing Clin Electrophysiol 2012;35:e87–90.Find this resource:

Reyes G, Schwartz PH, Newth CJ, Eldadah MK. The pharmacokinetics of isoproterenol in critically ill pediatric patients. J Clin Pharmacol 1993;33:29–34.Find this resource:



Isosorbide has, in the past, sometimes been used as an osmotic agent to control hydrocephalus in infancy in order to prevent or delay the need for shunt surgery. There are limited data to support its use. The same osmotic properties have also been used to treat glaucoma in older patients but again other treatments have superseded its use.


Isosorbide is an inert sugar (1,4:3,6-dianhydro-D-sorbitol) which acts as an osmotic agent when given intravenously in much the same way as mannitol. It is thought to be capable of reducing the formation of cerebrospinal fluid without inducing an excessive diuresis. Hypernatraemia may occur, especially if the fluid intake is inadequate. Many children dislike the taste (particularly at first). Possible adverse effects (all of which are reversible on stopping the drug) include hypernatraemia, acidosis, weight loss, vomiting, and diarrhoea, but experience suggests that, with the dose recommended here, such problems are uncommon.

It was first suggested in the 1970s that isosorbide might delay or abolish the need for shunt surgery in some children with congenital hydrocephalus with or without spina bifida as long as the condition is not deteriorating rapidly and the cerebral mantle is at least 15 mm thick. The only formal trial of its role in children with spina bifida has concluded that, although it can delay the need for shunt placement for two to three months, it makes no clear long-term difference to the number finally requiring shunt placement. A preliminary report suggested that it is of value in at least delaying the need for shunt surgery in children with post-haemorrhagic hydrocephalus; however, no controlled study of its use in the management of such children has yet been published.

In the United States, oral glycerol, or a combination of acetazolamide (see similar web archive) with or without furosemide, was more widely used in the first-line management of post-haemorrhagic hydrocephalus, until a UK trial has cast serious doubt on the wisdom of such treatment in 2001.


The standard starting dose is 8 g/kg per day by mouth given in divided doses every four to eight hours. The sugar has a slightly bitter after taste and is best given, therefore, with feeds. Lower doses can sometimes be used for maintenance purposes, but doses of up to 12 g/kg per day have been used for a few weeks without side effects. Medication is usually only withdrawn gradually (unless there is a shunt present capable of relieving any acute change in cerebrospinal fluid (CSF) pressure).


Pharmacies can prepare a solution containing 1 g per mL with a one-year shelf life.


Kulshrestha OP, Mittal RN. Isosorbide and intraocular pressure. Br J Ophthalmol 1972;56:439–41.Find this resource:

Liptak GS, Gellerstedt ME, Klionsky N. Isosorbide in the medical management of hydrocephalus in children with myelodysplasia. Dev Med Child Neurol 1992;34:150–4.Find this resource:

Lorber J, Salfield S. Lonton T. Isosorbide in the management of infantile hydrocephalus. Dev Med Child Neurol 1983;25:502–11.Find this resource:

Lorber J. Isosorbide in the treatment of infantile hydrocephalus. Observations with a new drug. Clin Pediatr (Phila) 1975;14:916–19.Find this resource:

Lorber J. Isosorbide in treatment of infantile hydrocephalus. Arch Dis Child 1975;50:431–6.Find this resource:

Shurtleff DB, Hayden PW. The treatment of hydrocephalus with isosorbide, and oral hyperosmotic agent. J Clin Pharmacol New Drugs 1972;12:108–14.Find this resource:

Shurtleff DB, Hayden PW, Weeks R, Laurence KM. Temporary treatment of hydrocephalus and myelodysplasia with isosorbide: preliminary report. J Pediatr 1973;83:651–7.Find this resource:



Mannitol is used to prevent and minimize the damage caused by acute cerebral trauma. Its utility in managing post-anoxic cerebral oedema is less clearly established. Mannitol is sometimes used in adults to induce the forced diuresis of renally excreted poisons.


Mannitol is a relatively inert hexahydric alcohol related to mannose and isomeric with the sugar sorbitol. It is rapidly excreted in the urine; very little is metabolized. Mannitol has two main mechanisms of action; immediately after bolus administration it expands the circulating volume, decreasing blood viscosity, and thus increasing cerebral blood flow and cerebral oxygen delivery. Osmotic properties then take effect 15–30 minutes later when it sets up an osmotic gradient and draws water out of oedematous neurones.

Mannitol has been used in eclampsia (although there was no major effect) and there are other reports of use during pregnancy in the emergency treatment of raised intracranial pressure. Mannitol crosses the placenta by diffusion but there are no reports of effects on the fetus. Teratogenicity studies do not appear to have been performed.

Three early studies, published by Cruz and colleagues in 2001, 2002, and 2004, suggested that the rapid administration of a high intravenous dose of mannitol could reduce the risk of death or serious disability in adults with signs suggestive of brain swelling as a result acute head injury. These trials, involving 363 patients, suggested that treatment more than halved the number of patients who were dead, and the number who were disabled six months later. They were the first formal controlled trials of such a strategy to be conducted, although there had been many observational studies showing that mannitol, by acting as an osmotic diuretic, can lower intracranial pressure. Such dramatic results attracted attention and further investigation suggested that the results—all from a single institution that had no record of ever employing the lead investigator—were fabricated (see web commentary). The most recent Cochrane review of mannitol use in this situation excludes these studies and draws rather different conclusions; rather, the evidence seems to suggest that mannitol may have some benefit when used as part of ‘intracranial pressure-directed’ therapy but not in other situations.

There are few data regarding the use of mannitol in children and even less in infants. Current guidelines recommend the use of hypertonic sodium chloride rather than mannitol for head-injured paediatric patients with raised intracranial pressure. Whilst 7.5% and 23.4% sodium chloride solutions are available, these require central access; 3% sodium chloride can be given safely through a peripheral intravenous line at a dose of 6 mL/kg over 15 minutes or as a continuous infusion of 0.1–1 mL/kg/hour to maintain an intracranial pressure of less than 20 mmHg. If hypertonic sodium chloride is unavailable then mannitol may be used.

Hypoxic ischaemic encephalopathy (HIE)

Before the advent of therapeutic hypothermia, mannitol was sometimes used in babies with hypoxic ischaemic encephalopathy. Closer examination of the studies suggested that significant cerebral damage also occurred in the absence of any raised intracranial pressure. Whilst mannitol seemed to reduce the intracranial pressure, it became increasingly clear that the rise in pressure usually only develops after severe damage has already occurred. Accordingly, there appears to be no role for mannitol in this situation.


When used to reduce intracranial pressure mannitol would be given at a dose of 0.25–1.5 g/kg (1.25–7.5 mL/kg of a 20% solution) intravenously over 30–60 minutes through a filter to trap any small crystals that may have formed into an existing infusion of glucose or glucose and sodium chloride. Treatment can be repeated once or twice after an interval of four to eight hours if necessary. Do not mix mannitol with any other drug.


Bags containing 500 mL of 20% mannitol in water costing £6.30 each are available. The bags should be stored at 20–30 °C to prevent crystallization: if this does occur warm the bag to 60 °C and then cool to blood temperature before use. The manufacturers have never endorsed use in children under the age of 12 years.


Adhikari M, Moodley M, Desai PK. Mannitol in neonatal cerebral oedema. Brain Dev 1990;12:349–51. [RCT]Find this resource:

Bennett TD, Statler KD, Korgenski EK, et al. Osmolar therapy in pediatric traumatic brain injury. Crit Care Med 2012;40:208–15.Find this resource:

Demir BC, Ozerkan K, Ozbek SE, et al. Comparison of magnesium sulfate and mannitol in treatment of eclamptic women with posterior reversible encephalopathy syndrome. Arch Gynecol Obstet 2012;286:287–93.Find this resource:

Diringer MN, Scalfani MT, Zazulia AR, et al. Effect of mannitol on cerebral blood volume in patients with head injury. Neurosurgery 2012;70:1215–18.Find this resource:

Kamel H, Navi BB, Nakagawa K, et al. Hypertonic saline versus mannitol for the treatment of elevated intracranial pressure: a meta-analysis of randomized clinical trials. Crit Care Med 2011;39:554–9.Find this resource:

Kochanek PM, Carney N, Adelson PD, et al. Guidelines for the acute medical management of severe traumatic brain injury in infants, children, and adolescents—second edition. Pediatr Crit Care Med 2012;13 (Suppl 1):S1–82.Find this resource:

Levene MI, Evans DH. Medical management of raised intracranial pressure after severe birth asphyxia. Arch Dis Child 1985;60:12–16.Find this resource:

Levene MI, Evans DH, Forde A, et al. Value of intracranial pressure monitoring of asphyxiated infants. Dev Med Child Neurol 1987;29:311–19.Find this resource:

Marchal C, Leveau P, André M, et al. The treatment of neonatal cerebral distress. Action of repeated perfusions of mannitol. Pediatrie 1972;27:709–19.Find this resource:

Piper BJ, Harrigan PW. Hypertonic saline in paediatric traumatic brain injury: a review of nine years’ experience with 23.4% hypertonic saline as standard hyperosmolar therapy. Anaesth Intensive Care 2015;43:204–10.Find this resource:

Roberts I, Smith R, Evans S. Doubts over head injury studies. Brit Med J 2007;334:392–4 (1ee also 378–9).Find this resource:

See also the relevant Cochrane reviews

Prabhakar H, Singh GP, Anand V, et al. Mannitol versus hypertonic saline for brain relaxation in patients undergoing craniotomy. Cochrane Database Syst Rev 2014;7:CD010026. Available at: this resource:

Wakai A, McCabe A, Roberts I, et al. Mannitol for acute traumatic brain injury. Cochrane Database Syst Rev 2013 Aug;8:CD001049. Available at: this resource:



Protease inhibitors like nelfinavir are used with other drugs, to control human immunodeficiency virus (HIV) infection. Nelfinavir has many of the same properties of lopinavir with ritonavir (q.v.) and was for some time the only protease inhibitor available in liquid formulation suitable for administration to babies. Low levels of use, and contamination of supplies, led the manufacturers to discontinue its production in Europe but use continues in other parts of the world. Early studies probably used too low a dose; infants probably need at least 75 mg/kg twice by mouth, but the optimum dose remains unclear.


Nelfinavir binds to HIV-protease causing the formation of immature viral particles that are incapable of infecting other cells. It came into general clinical use in the late 1990s. Oral absorption in infants can be highly variable. Virological failure (i.e. evidence of viral replication whilst on treatment) was an issue with many early studies of this drug where doses of 20–30 mg/kg three times daily were used in older children, and eventually much higher doses were introduced.

Like other protease inhibitors, nelfinavir is metabolized by hepatic cytochrome system. It is first converted by CYP2C19 to the active metabolite M8, and then both M8 and nelfinavir are eliminated through CYP3A4 and excreted in the faeces. The elimination half-life in adults is ~five hours but ~3.6 hours in infants. The antiviral response to nelfinavir is significantly less in children < two years than in older children and infants have higher variability in plasma concentrations thought to be due to both poor absorption and more rapid metabolism.

Fetal and infant implications of maternal treatment

Nelfinavir crosses the placenta and rodent teratogenicity studies are reassuring. Registries of use in human pregnancies have yet to find any consistent effects. Nelfinavir clearance is significantly increased during late pregnancy (the elimination half-life is ~3.7 hours) and some groups have reported virological breakthroughs or suboptimal blood levels during pregnancy. However, the clinical impact of pregnancy-induced sub-exposure remains unclear.

Breastfeeding is not recommended in HIV-infected women where formula is available to reduce the risk of neonatal transmission. In countries where formula is not readily available or safe, ongoing use during breastfeeding is used is used to reduce transmission. Small amounts of nelfinavir pass into breast milk and low (sub-therapeutic) levels can be detected in babies, which have the potential nonetheless to cause anaemia in the exposed baby.

The use of nelfinavir may, like some other antiretrovirals, cause suppression of viral replication such that standard tests give a ‘negative’ result. Repeat testing is recommended by the World Health Organization (WHO) in all such infants six weeks after breast feeding (and thus exposure to the drug) ceases.

Drug interactions

The protease inhibitors are best given with food. Since nelfinavir is part metabolised by CYP3A4, its clearance is increased by a wide range of other drugs including carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampicin, and theophylline). Protease inhibitors also inhibit the clearance of other drugs; co-treatment with drugs that have a narrow therapeutic range (e.g. antihistamines, benzodiazepines, rifampicin, amiodarone, and flecainide) is discouraged because of a variable and unpredictable reduction in clearance of these drugs. Digoxin levels are variably affected. See:

Supply issues

A number of problems have beset nelfinavir supply, at least in the United Kingdom and Europe. Nelfinavir marketing was suspended in July 2007 due to ethyl mesilate (a known mutagen and carcinogen) contamination and, more recently, due to low demand and the exclusion of nelfinavir from most treatment regimes, Roche elected to discontinue manufacture and allowed its European license to lapse. At present it is no longer available in the United Kingdom or the rest of Europe.

The US license allows the use of nelfinavir in children two years of age and older at a recommended dose is 45–55 mg/kg twice daily or 25–35 mg/kg three times daily with food. Nelfinavir remains available in South America and some Asian countries.


New information on optimum management becomes available so frequently that communication with a Paediatric HIV/Infectious Diseases Specialist is essential. The diagnosis and management must also be discussed with, and supervised by, someone with extensive experience of this condition.

If use is recommended, give 50–75 mg/kg twelve hours apart.


Nefinavir no longer available in the United Kingdom. It was available as a powder containing 50 mg of nelfinavir in 1 gram. The powder was mixed, just before use with water, milk, ice-cream, or puddings. An alternative was to crush 250 mg tablets as there were probably more palatable.


Dryden-Peterson S, Shapiro RL, Hughes MD, et al. Increased risk of severe infant anemia following exposure to maternal HAART, Botswana. J Acquir Immune Defic Syndr 2011;56:428–36.Find this resource:

Fang A, Valluri SR, O’Sullivan MJ, et al. Safety and pharmacokinetics of nelfinavir during the second and third trimesters of pregnancy and postpartum. HIV Clin Trials 2012;13:46–59.Find this resource:

King CC, Kourtis AP, Persaud D, et al. Delayed HIV detection among infants exposed to postnatal antiretroviral prophylaxis during breastfeeding. AIDS 2015;29:1953–61.Find this resource:

Mirochnick M, Nielsen-Saines K, Pilotto JH, et al. Nelfinavir and lamivudine pharmacokinetics during the first two weeks of life. Pediatr Infect Dis J 2011;30:769–72.Find this resource:

Mirochnick M, Stek A, Acevedo M, et al. Safety and pharmacokinetics of nelfinavir coadministered with zidovudine and lamivudine in infants during the first 6 weeks of life. J Acquir Immune Defic Syndr 2005;39:189–94.Find this resource:

Nielsen-Saines K, Watts DH, Veloso VG, et al. Three postpartum antiretroviral regimens to prevent intrapartum HIV infection. N Engl J Med 2012;366:2368–79. [RCT]Find this resource:

Scherpbier HJ, Bekker V, van Leth F, et al. Long-term experience with combination antiretroviral therapy that contains nelfinavir for up to 7 years in a pediatric cohort. Pediatrics 2006;117:e528–36.Find this resource:

Taylor GP, Clayden P, Dhar J, et al. British HIV Association guidelines for the management of HIV infection in pregnant women 2012. HIV Med 2012;13 (Suppl 2):87–157.Find this resource:

van Heeswijk RPG, Khaliq Y, Gallicano KD, et al. The pharmacokinetics of nelfinavir and M8 during pregnancy and post partum. Clin Pharmacol Ther 2004;76:588–97.Find this resource:

van Hoog S, Boer K, Nellen J. Transplacental passage of nevirapine, nelfinavir and lopinavir. Netherlands J Med 2012:70;102–3.Find this resource:

Weidle PJ, Zeh C, Martin A, et al. Nelfinavir and its active metabolite, hydroxy-t-butylamidenelfinavir (M8), are transferred in small quantities to breast milk and do not reach biologically significant concentrations in breast-feeding infants whose mothers are taking nelfinavir. Antimicrob Agents Chemother 2011;55:5168–71.Find this resource:



Netilmicin was used for many years as an alternative to gentamicin (q.v.) in the treatment of Gram-negative bacterial infection. Although it is generally accepted that netilmicin was less ototoxic then gentamicin, sales slowly declined, and all commercial production eventually ceased in 2008.


Netilmicin is an aminoglycoside antibiotic first developed in 1976, it is a semi-synthetic derivative of the aminoglycoside, sisomicin which is produced by Micromonospora inyoensis, but which has not seen clinical use in the United Kingdom or North America While netilmicin is sometimes effective against organisms that are resistant to gentamicin, such as coagulase negative staphylococci, it is rather less active against Pseudomonas.

Like other aminoglycosides, netilmicin is not metabolized further in the body but is passively filtered by the glomerulus and concentrated in the urine. The resultant half-life is inversely related to postconceptional age. It also falls significantly during the first week after delivery. It averages 15 hours at birth in babies of less than 28 weeks gestation, but falls to six hours in term babies more than a week old. All aminoglycosides are potentially toxic to the ear and kidney. Damage to the renal tubules builds up with time (and can even produce a Bartter-like syndrome) but this is reversible when treatment is stopped, and seldom severe. Simultaneous treatment with vancomycin can increase these problems. Damage to the ear is uncommon in young children, but this can cause balance problems as well as high-tone deafness, and this can become permanent if early symptoms go unrecognized (as they will in the neonatal period). While many units measure blood levels routinely in order to minimize this risk, it is at least as important to avoid simultaneous treatment with furosemide, and to try to stop treatment after seven to ten days. All aminoglycosides marketed in North America come with routine guidance about the need to give any intravenous dose slowly over 30 minutes, but no such advice is issued with any of the products on sale in Europe.

There are theoretical reasons for not giving a β‎-lactam penicillin or cephalosporin at precisely the same time as an aminoglycoside. Many aminoglycosides combine chemically with equimolar amounts of most penicillins. Such inactivation has been well documented in vitro and is the basis for the advice that these antibiotics should never be mixed together. Netilmicin is inactivated to a lesser degree than gentamicin or tobramycin.

Fetal and infant implications of maternal treatment

All aminoglycosides cross the placenta (producing fetal levels that are about half the maternal level), but streptomycin and kanamycin are the only products known to have caused ototoxicity in utero. All have to be given intravenously or intramuscularly. Too little is absorbed from the gut (oral bioavailability is < 1%) for there to be any contraindication to maternal use during lactation (although the baby’s gut flora could be altered).



Give 6 mg/kg intravenously or intramuscularly to babies less than four weeks old, and 7.5 mg/kg to babies older than this. A slow 30-minute infusion is not necessary when the drug is given intravenously.


Give a dose once every 36 hours in babies of less than 32 weeks gestation in the first week of life. Give all other babies a dose once every 24 hours unless renal function is poor. Check the trough level (as below) and increase the dosage interval by 12 hours if the trough level is more than 2 mg/L.

Blood levels

Take blood for a trough blood level just before the fourth dose is given (or, preferably, before the third dose is given in babies less than a week old and in babies with poor renal function). The peak level only needs to be measured when a non-standard treatment policy is used. Collect serum immediately before and (if necessary) 60 minutes after intravenous administration (remembering to calculate the time taken for the drug to pass down the giving set) and give the laboratory details of every antibiotic being used. Aim for a peak concentration in the serum of 9–12 mg/L, and a trough level of about 1 mg/L. (1 mg/L = 2.1 micromol/L). Extend the dosage interval by 12 hours if the trough level exceeds 2 mg/L. A high trough level can be a very helpful early sign of poor renal function, but a low level does not mean that ototoxicity will not develop. Samples should be spun and frozen if not analysed promptly.


Ampoules containing 15 mg of netilmicin in 1.5 mL cost £1.40 each when last commercially available.


Borradori C, Fawer C-L, Buclin T, et al. Risk factors of sensorineural hearing loss in preterm infants. Biol Neonat 1997;17:1–10.Find this resource:

Brooks JR, Marlow N, Reeves BC, et al. Use of one-daily netilmicin to treat infants with suspected sepsis in a neonatal intensive care unit. Biol Neonat 2004;86:170–5.Find this resource:

Ettlinger JJ, Bedford KA, Lovering AM, et al. Pharmacokinetics of once-a-day netilmicin (6 mg/kg) in neonates. J Antimicrob Chemother 1996;38:499–505.Find this resource:

Klingenberg C, Småbrekke L, Lier T, et al. Validation of a simplified netilmicin dosage regimen in infants. Scand J Infect Dis 2004;36:474–9.Find this resource:

Koren G, James A, Perlman M. A simple method for estimation of glomerular filtration rate by gentamicin pharmacokinetics during the routine monitoring of the newborn. Clin Pharmacol Ther 1985;38:680–5.Find this resource:

Treluyer JM, Merle Y, SamLali A, et al. Population pharmacokinetic analysis of netilmicin in neonates and infants with use of a non-parametric method. Clin Pharmacol Ther 2000;67:600–9.Find this resource:



Sodium nitroprusside is a direct, very rapid-acting, peripheral vasodilator often used to reduce afterload when left ventricular function is impaired. It can be used to control systemic hypertension, and has been used, experimentally to produce selective pulmonary vasodilatation.


Sodium nitroprusside is a potent vasodilator, developed in 1951, that is now known to cause smooth muscle relaxation by acting as a direct nitric oxide donor. At low doses nitroprusside reduces systemic vascular resistance and increases cardiac output. This may be associated with a slight increase in heart rate, but significant tachycardia is unusual. It decreases right atrial pressure, pulmonary capillary wedge pressure, and pulmonary vascular resistance. However, a high intravenous dose of nitroprusside can produce serious systemic hypotension and can also exacerbate myocardial ischaemia (a tendency aggravated by volume depletion). When directed specifically at the pulmonary vasculature by nebulization it can cause very marked pulmonary vasodilation without having any detectable systemic effect. One study has suggested that such treatment can be as effective, in the short term, as treatment with nitric oxide (q.v.) in babies with hypoxic respiratory failure. It is also cheaper, and use does not require specialist equipment.

Enzymatic breakdown of one molecule of sodium nitroprusside releases five cyanide molecules. These are quickly metabolized to thiocyanate in the liver and then slowly excreted by the kidneys (half-life four days). Tissue levels exceed plasma levels (VD about 3 L/kg). Prolonged or high-dose infusions of nitroprusside, or the presence of hepatic or renal impairment, can cause a dangerous accumulation of these toxic products. Prolonged use can also lead to hypothyroidism as thiocyanate inhibits iodine uptake into the thyroid gland.

The manufacturers have not yet issued any advice about the use of nitroprusside in children, but toxic side effects have never been described at infusion rates of 2 microgram/kg per minute, and rates of up to 8 microgram/kg per minute are generally considered safe. The cerebral vasodilatation caused by nitroprusside may be undesirable in some neonates, but many cardiothoracic centres routinely use this drug in the initial control of the paradoxical hypertension sometimes seen after coarctectomy. The rapidity of its action and subsequent degradation, make nitroprusside a relatively safe drug to use with due monitoring in an intensive care setting. Continuous (and, in particular, invasive) blood pressure monitoring is advisable.

Fetal and infant implications of maternal treatment

Little is known about the long-term use or safety of nitroprusside when prescribed during pregnancy or lactation, but short-term use to control pregnancy-induced hypertension seems safe even though it causes a 30% reduction in uterine blood flow.



Begin by giving an infusion of 500 nanogram/kg/minute of nitroprusside. Monitor systemic blood pressure and, if required, increase the rate of infusion cautiously in steps of 200 nanograms/kg/minute to a maximum rate of 8 microgram/kg/minute. If the infusion is required for longer than 24 hours try to decrease the rate to below 4 microgram/kg/minute to minimize the accumulation of toxic metabolites.


Giving a nebulised solution containing 25 mg of nitroprusside dissolved in 2 mL 0.9% sodium chloride into the ventilator gas circuit causes very effective, short lasting, selective pulmonary vasodilatation.


Nitroprusside can be added (terminally) to an intravenous line containing atracurium, dobutamine and/or dopamine, glyceryl trinitrate, midazolam, or milrinone.


Tachycardia, arrhythmia, sweating, and acidosis suggest cyanide toxicity, especially after sustained treatment in a patient with renal impairment. Do not wait until cyanide and thiocyanate levels are available. Correct the acidosis and give 0.3 mL/kg of 3% sodium nitrite intravenously (unless there is overt cyanosis) followed by 0.8 mL/kg of a 50% solution of intravenous sodium thiosulfate.

Supply and administration

Sodium nitroprusside is available from ‘special-order’ manufacturers or specialist importing companies as a 50 mg vial of lyophilized sodium nitroprusside powder for reconstitution with 5 mL of solvent (anhydroglucose and water for injections). When reconstituted this produces a solution containing 10 mg/mL.

Take 0.5 mL (5 mg) of this solution and dilute up to 10 mL with 5% glucose (500 microgram/mL). Then take 3 mL of this dilute solution for each kilogram the baby weighs and further dilute to 25 mL with 5% glucose (60 microgram/kg per mL). Infusing this solution at 1 mL/hour will give 1000 nanogram/kg/minute (i.e. 1 microgram/kg/minute).

Shade the infusate from light, because this causes nitroprusside to break down to cyanide and ferrocyanide. Prepare a fresh infusion once every 24 hours. Store ampoules in the dark (discarding any that become brownish).


Deliu AG, Sanneerappa PBJ, Franklin O, et al. Sodium nitroprusside, a lifesaving treatment for neonatal hypertension: an Irish experience. BMJ Case Rep 2018 Mar 28;2018.Find this resource:

Hammer GB, Lewandowski A, Drover DR, et al. Safety and efficacy of sodium nitroprusside during prolonged infusion in pediatric patients. Pediatr Crit Care Med 2015;16:397–403.Find this resource:

Mestan KKL, Carlson AD, White M, et al. Cardiopulmonary effects of nebulized sodium nitroprusside in term infants with hypoxic respiratory failure. J Pediatr 2003;143:640–3.Find this resource:

Motta P, Mossad E, Toscana D, et al. Comparison of phenoxybenzamine and sodium nitroprusside in infants undergoing surgery. J Cardiothorac Vasc Anesth 2005;19:54–9.Find this resource:

Palhares DB, Figueiredo CS, Moura AJM. Endotracheal inhalatory sodium nitroprusside in severely hypoxic newborns. J Perinat Med 1998;26:219–24.Find this resource:

Thomas C, Svehla L, Moffett BS. Sodium-nitroprusside-induced cyanide toxicity in pediatric patients. Expert Opin Drug Saf 2009;8:599–602.Find this resource:



Although not widely available, papaverine has been used experimentally in a few centres to reduce the risk of vasospasm and prolong the lifespan of peripheral arterial catheters. Glyceryl trinitrate ointment (q.v.) will sometimes correct any vasospasm that does occur.


Papaverine is an alkaloid present in opium although it is not related, either chemically or pharmacologically, to the other opium alkaloids. It was first isolated in 1848 and was briefly in vogue as a vasodilator and antispasmodic in the 1920s prior to the development of synthetic analogues of atropine. It has a direct relaxant effect on smooth muscle, probably because it inhibits phosphodiesterase, and it was frequently used for a time by intracavernosal injection in the treatment of male impotence.

It can, however, cause general vasodilatation, and it was shown, in a randomised controlled trial involving over 200 children in 1993, to extend the functional life of peripheral arterial cannulae. Such lines also lasted 40% longer in a recent neonatal trial. However, since this study only involved 141 babies, more studies will be needed before we can be sure that this form of prophylaxis is not only effective but also safe when used in the preterm baby. Its use in the first few days of life certainly needs to be approached with some caution because vasodilatation could have adverse cerebrovascular consequences. A sustained low-dose intra-arterial infusion of tolazoline has been used for the same purpose, and has also been used to abolish the acute ‘white leg’ occasionally caused by femoral artery spasm following umbilical artery catheterization. Low-dose heparin (q.v.) has been shown to extend the ‘life’ of intravascular lines in adults, but the only neonatal trials done to date have been too small to show similar benefit with any certainty. The need for invasive arterial sampling has been much reduced by recent developments in pulse oximetry, and systolic blood pressure can also be monitored non-invasively using Doppler sphygmomanometry.

Adverse effects of papaverine are uncommon, but include flushing, hypotension, and gastrointestinal disturbances. High doses can cause cardiac arrhythmia. The drug is rapidly metabolized by the liver and excreted in the urine, the adult half-life being variable, but usually only a little more than one hour. Nothing is known about the time course of drug elimination in the neonatal period, or the effect of maternal use during pregnancy or lactation.

Take care not to confuse papaveretum for papaverine.

Papaverine can be confused with papaveretum, a preparation containing a mixture of opium alkaloids (including morphine and codeine as well as papaverine hydrochloride) with potentially fatal consequences.


A slow syringe-controlled infusion can be used to help sustain catheter patency. 100 microgram/mL of papaverine made up as described below, and infused at a rate of 1 mL per hour (with or without additional heparin), can prolong the functional life of a peripheral arterial line. This fluid must not be used to flush the catheter through after sampling: any such bolus of papaverine could cause marked vasodilatation.


Papaverine was co-infused with heparin at a rate of 1 mL/hour in both the controlled trials referred to earlier.

Supply and administration

Papaverine is an unlicensed product but may be imported from a number of countries by the pharmacy to special order. Ampoules contain 30 mg in 2 mL. To obtain a solution containing approximately 100 microgram/mL take 5 mg (0.3 mL) of papaverine, dilute to 50 mL with glucose, glucose with sodium chloride, or sodium chloride, and infuse at a rate of not more than 1 mL per hour using a syringe pump.


Griffin MP, Kendrick AS. Does papaverine prevent failure of arterial catheters in neonates? [Abstract] Pediat Res 1995;37:207A.Find this resource:

Griffin MP, Siadaty MS. Papaverine prolongs patency of peripheral arterial catheters in neonates. J Pediatr 2005;146:62–5. [RCT]Find this resource:

Heulitt MJ, Farrington EA, O’Shea TM, et al. Double blind, randomised, controlled trial of papaverine-containing infusions to prevent failure of arterial catheters in pediatric patients. Crit Care Med 1993;21:825–9. [RCT]Find this resource:

Lemke RP, al-Saedi SA, Belik J, et al. Use of tolazaline to counteract vasospasm in peripheral arterial catheters in neonates. Acta Paediatr 1996;85:1497–8.Find this resource:

Panigrahy N, Kumar PP, Chirla DK, Vennapusa SR. Papaverine for ischemia following peripheral arterial catheterization in neonates. Indian Pediatr 2016;53:169.Find this resource:



Paraldehyde provides a very effective way of terminating persistent non-hypoglycaemic convulsions especially if there is no response to one of the drugs commonly used first—intravenous phenobarbital (q.v.) in the neonate, or a benzodiazepine (such as buccal midazolam, intranasal lorazepam, or rectal diazepam) in later infancy.

Paraldehyde has largely fallen out of favour, largely because of the inconvenience of its administration and storage.


Paraldehyde, a polymer of acetaldehyde, has been used for a century as a sedative-hypnotic and for seizure control. It is a potent anticonvulsant capable of controlling seizures refractory to phenobarbital, phenytoin, and the benzodiazepines without causing respiratory depression. It exerts its action rapidly and is then eliminated from the body with a half-life that which is rather variable, but only a little shorter than that of most other anticonvulsants used in the neonatal period.

Drug elimination is by oxidation by hepatic cytochromes to acetaldehyde and carbon dioxide and also by direct excretion through the lungs. Dispersal into body tissues is very variable (VD ~4 L/kg). The half-life in babies is also very variable (8–27 hours) but generally rather longer than in children (7½ hours) and adults (6 hours). The dose given does not need to be modified in babies with kidney failure because renal clearance is negligible, but the drug’s variable and prolonged half-life probably makes repeated dosing unwise in the first few weeks of life.

The management of babies in whom electroencephalogram (EEG) evidence of seizure activity persists despite treatment with both phenobarbital and phenytoin (q.v.) is in urgent need of further study. Paraldehyde has fallen out of favour but might well turn out to be quite effective if a blood level of 100 mg/L can be achieved.

The intramuscular route was once widely used in babies, but standard texts now generally consider the rectal route safer. Large intramuscular injections are certainly painful, and they can cause an unpleasant sterile abscess with subsequent muscle and/or nerve damage, but such problems are very uncommon following the deep intramuscular injection of volumes not exceeding 1mL (which is all that any neonate should need), and the response to an intramuscular injection is much quicker than the response to rectal administration.

Rectal diazepam was once widely used to control seizures in a home setting, but a dose of liquid lorazepam or midazolam (q.v.) given into the nose or mouth is usually equally effective and families often find this approach more acceptable. However, paraldehyde provides a very effective way of stopping prolonged seizure activity in any setting if intravenous access proves difficult.

Fetal and infant implications of maternal treatment

Paraldehyde crosses the placenta but there is nothing to suggest that its use is hazardous in pregnancy. There are no reports of use during lactation.



Give a single 0.4 mL/kg dose of paraldehyde mixed with an equal volume of olive oil (or mineral oil).


Give 0.2 mL/kg by deep intramuscular injection. A second identical dose can be given if seizures persist or recur, but no further doses should be given to neonate after that for 36 hours because the half-life is unpredictable.


Paraldehyde can be given as an intravenous infusion, but the use of this route is now generally discouraged, and it is not really necessary given the drug’s long half-life in the neonatal period. To give 0.4 mL/kg of paraldehyde (the maximum safe dose) as an intravenous infusion, dilute 2.5 mL of paraldehyde to 50 mL with 5% glucose and then give 4 mL/kg of this solution over just two hours as a slow continuous infusion protected from light.

Supply and administration


Amber glass bottles which contain 15 mL of paraldehyde already mixed with 15 mL of olive oil are available on special order in the United Kingdom for rectal administration. Ampoules of pure paraldehyde (containing 1 g/mL) are still available in some countries but are no longer marketed in the United Kingdom. Never use either product if there is brown discolouration, or if there is a sharp pungent odour of acetic acid when the container is first opened. Keep all products below 25 ºC during storage.


Paraldehyde reacts chemically with rubber and with most plastics (polythene and polypropylene syringes being more resistant than those made of polyvinyl chloride (PVC)), but it can be given using any plastic syringe as long as it is injected just as soon as it is drawn up. However, a polypropylene syringe (such as a Plastipak® syringe made by Becton Dickinson), and a polypropylene extension set (such as one of the products marketed by Vygon) must be used if a sustained intravenous infusion is to be given.


Ahmad S, Ellis JC, Kamwendo H, et al. Efficacy and safety of intranasal lorazepam versus intramuscular paraldehyde for protracted convulsions in children: an open randomised trial. Lancet 2006;367:1591–7. [RCT]Find this resource:

Armstrong DL, Battin MR. Pervasive seizures caused by hypoxic-ischaemic encephalopathy: treatment with intravenous paraldehyde. J Child Neurol 2001;16:915–17.Find this resource:

Giacoia G P, Gessner I K, Zaleska MM, et al. Pharmacokinetics of paraldehyde disposition in the neonate. J Pediatr 1984;104:291–6.Find this resource:

Johnson CE, Vigoreaux JA. Compatibility of paraldehyde with plastic syringes and needle hubs. Am J Hosp Pharm 1984;41:306–8.Find this resource:

Koren G, Butt W, Tajchgot P, et al. Intravenous paraldehyde for seizure control in newborn infants. Neurology 1986;36:108–11.Find this resource:

Rowland AG, Gill AM, Stewart AB, et al. Review of the efficacy of rectal paraldehyde in the management of acute and prolonged tonic-clonic convulsions. Arch Dis Child 2009;94:720–3.Find this resource:

Shorvon S. The historical evolution of, and the paradigms shifts in, the therapy of convulsive status epilepticus over the past 150 years. Epilepsia 2013;54 (Suppl 6):64–7.Find this resource:

Tulloch JK, Carr RR, Ensom MH. A systematic review of the pharmacokinetics of antiepileptic drugs in neonates with refractory seizures. J Pediatr Pharmacol Ther 2012;17:31–44.Find this resource:



Penicillamine is used to treat heavy metal poisoning and is also used in the long-term management of severe rheumatoid arthritis and Wilson’s disease.

Two small studies of prophylactic penicillamine have suggested that it may have the potential to reduce the risk of retinopathy of prematurity (ROP) in at-risk babies but this approach has not been widely adopted.


Penicillamine is obtained by controlled hydrolysis of penicillin. It was discovered in 1943 and first came into clinical use in 1956 because of its ability to bind with (chelate) lead, copper, mercury, iron, and other heavy metals to form a stable complex that is then excreted in the urine. It is well absorbed when taken by mouth and mostly metabolized by the liver prior to slow biphasic excretion in the urine (the plasma half-life being one to six hours). No complications have been seen with short-term oral treatment, but sustained use has been associated with skin problems and marrow dysfunction, with nephrotic syndrome caused by a membranous nephropathy, and, occasionally, with hypothyroidism.

Use in cystinuria

Penicillamine is sometimes used in children with cystinuria (a recessively inherited defect of dibasic amino acid transport in the proximal tubule) if simpler measures, such as a high fluid intake and the use of sodium bicarbonate to keep the urine alkaline (pH predominantly > 6), do not suffice to prevent stone formation. Use the minimum dose needed to keep the urinary cystine concentration reliably below its solubility limit (300 mg/L).

Use in Wilson’s disease

Treatment with 20 mg/kg a day is routinely used in Wilson’s disease, a recessively inherited metabolic disorder associated where mutations in the ATP7B gene cause excessive copper accumulation. Whilst most patients present with liver disease in their teens, clinical presentation with raised transaminases has been reported as young as nine months of age.

Lifelong treatment with penicillamine has revolutionized the management of a previously fatal condition. A similar dose may counteract the copper poisoning that seems to be responsible for Indian childhood cirrhosis, if started early enough. Variable amounts may be needed in the management of rheumatoid factor positive juvenile chronic arthritis. Adverse effects are not uncommon, and can be severe, but usually resolve when the drug is discontinued.

Other uses

Early findings from two small Hungarian trials suggested that prophylactic, high-dose administration may significantly reduce the risk of ROP, either by impeding new vessel growth by reducing the bioavailability of vascular growth factors, or by acting as a free-radical oxygen scavenger (a property it shares with vitamin E (q.v.), which has also been used in much the same way). Other similar trials do not appear to support this.

Fetal and infant implications of maternal treatment

Reports exist of the use of penicillamine in more than 100 pregnancies. Successful outcomes are reported but so too are cases of congenital cutis laxa and other defects (micrognathia, contractures, and neurological abnormalities). Using a low dose (< 500 mg per day) seems to avoid these risks.

Penicillamine does not appear to enter breast milk but there is too little information to be proscriptive about breastfeeding and in the absence of further information it should probably be avoided.

Prophylaxis for retinopathy

The only trials of penicillamine use for this indication have used 100 mg/kg of penicillamine given intravenously once every eight hours for three days, and then 50 mg/kg once a day for two weeks.

Use in Wilson’s disease

Begin with penicillamine 20 mg/kg daily in two to three divided doses. Each dose should taken one hour before food. The dose may be increased to a maximum of 2 g per day

Monitoring long-term treatment

The care of patients requiring sustained treatment with penicillamine should be supervised by a clinician experienced in the management of metabolic disease. It is generally considered important to check the full blood count initially once a week and then monthly and to suspend treatment if the white cell count falls below 2.5 × 109/L, or the platelet count falls below 120 × 109/L. Nephrotoxicity with proteinuria is an occasional problem. Prednisolone has sometimes been given briefly if toxic symptoms develop.


Penicillamine is supplied as 125 mg and 250 mg tablets costing 80p and £1.58 each. Pharmacies can sometimes prepare a sugar-free 10 mg/mL suspension for oral use which is stable for four weeks if stored at 4 ºC. No commercial intravenous preparation is available at present.


Armer J, De Goede C. How to use tests for disorders of copper metabolism. Arch Dis Child Educ Pract Ed 2017;102:319–27.Find this resource:

Bavdekar AR, Bhave SA, Pradhan AM, et al. Long term survival in Indian childhood cirrhosis treated with D-penicillamine. Arch Dis Child 1996;74:32–5.Find this resource:

Christensen RD, Alder SC, Richards SC, et al. D-Penicillamine administration and the incidence of retinopathy of prematurity. J Perinatol 2007;27:103–11.Find this resource:

Dello Strologo L, Laurenzi C, Legato A, Pastore A. Cystinuria in children and young adults: success of monitoring free-cystine urine levels. Pediatr Nephrol 2007;22:1869–73.Find this resource:

Hanukoglu A, Curiel B, Berkowitz D, et al. Hypothyroidism and dyshormonogenesis induced by D-penicillamine in children with Wilson’s disease and healthy infants born to a mother with Wilson’s disease. J Pediatr 2008;153:864–6.Find this resource:

Ishak R, Abbas O. Penicillamine revisited: historic overview and review of the clinical uses and cutaneous adverse effects. Am J Clin Dermatol 2013;14:223–33.Find this resource:

Izumi Y. Can mothers with Wilson’s disease give her breast milk to their infant? Teikyo Med J 2012;35:17–24.Find this resource:

Oga M, Matsue N, Anai T, et al. Copper disposition of the fetus and placenta in a patient with untreated Wilson’s disease. Am J Obstet Gynecol 1993;169:196–8.Find this resource:

Rosa FW. Teratogen update: penicillamine. Teratology 1986;33:127–31.Find this resource:

Sánchez-Albisua I, Garde T, Hierro L, et al. A high index of suspicion: the key to the early diagnosis of Wilson’s disease in childhood. J Pediatr Gastroenterol Nutr 1999;28:86–90.Find this resource:

Tandon M, Dutta S, Dogra MR, et al. Oral D-penicillamine for the prevention of retinopathy of prematurity in very low birth weight infants: a randomized, placebo-controlled trial. Acta Paediatr 2010;99:1324–8. [RCT]Find this resource:

See also Cochrane review of use to prevent ROP

Qureshi MJ, Kumar M. D-Penicillamine for preventing retinopathy of prematurity in preterm infants. Cochrane Database Syst Rev 2013;9:CD001073. Available at: this resource:

Potassium iodate


Iodine is an essential trace element.

Larger doses of potassium iodate can be used, in an emergency, to block the uptake of radioactive iodine by the thyroid and thus reduce the later risk of thyroid cancer. Iodine inhibits the extra-thyroidal conversion of thyroxine (T4) to tri-iodothyronine (T3) and inhibits the thyroid secretion of these two hormones.

Nutritional factors

Iodine is necessary for thyroid hormone formation and is an essential trace element. Maternal goitre is common in areas of the world where the diet is deficient. In these areas, perinatal mortality is increased and cretinism (a syndrome characterized by spasticity, deaf mutism, intellectual deficit, and variable hypothyroidism) is common. Problems can be prevented by the routine addition of 10–80 parts per million of potassium iodate (or potassium iodide) to all cooking salt, but many countries have still not taken this step. A quarter of a billion of the world’s children are iodine deficient by World Health Organization (WHO) standards. Adequate intake is particularly critical during pregnancy, lactation and early childhood. A single prophylactic 500 mg injection of iodized poppyseed oil (containing ~38% w/w iodine) can be used in pregnancy in areas where cretinism is endemic. Subclinical deficiency can also occur in babies on parenteral nutrition on standard doses of Peditrace®.


In 1991, the UK Department of Health issued guidance on the use of iodine prophylaxis in the unlikely event of a nuclear accident causing radiation ‘fallout’ after the Chernobyl nuclear disaster in 1986 and the subsequent significant increase in cases of childhood thyroid cancer, first reported in Belarus in 1991. This was largely based on earlier advice from the WHO which was first published in 1989 and updated in 1999: available at Similar, updated, and more detailed advice was issued by the US Food and Drug Administration in late 2001 (see

Use of a stable iodine preparation can block uptake by the thyroid of inhaled radioactive iodine, reducing the subsequent risk of thyroid cancer (oral intake being minimized by appropriate restrictions on the use of contaminated food). Fresh meat and dairy products pose a particular problem if pasture is affected. Young children are at particular risk. Treatment cannot, of course, reduce the radiation dose from external radiation or from other radionuclides. Two 85 mg tablets of potassium iodate (containing the equivalent of 100 mg of stable iodine) will reduce exposure by half, even if this is only taken five hours after exposure to radioiodine.

Radiation hazard prophylaxis


Any adult in the vicinity of any incident (including pregnant and lactating women) in the United Kingdom are advised to take two 85 mg tablets of potassium iodate immediately any nuclear emergency is notified. This dose may need to be repeated daily if the hazard persists, but repeated dosing should be avoided in those who are pregnant or breastfeeding where possible.


Babies can, most conveniently, be given 0.1 mL of Lugol’s iodine (see below) where this is available. Otherwise, in an emergency, they may be given half an adult tablet of potassium iodate crushed in a teaspoon of jam or dissolved in a small quantity of milk or juice. Repeated doses should not, in general, be given in very young babies because there is some risk that this will cause hypothyroidism.

Subsequent management

Neonates given iodine will need to have their thyroid stimulating hormone (TSH) levels monitored and, if these are raised, their T4 levels checked, and appropriate replacement thyroxine offered as appropriate. Babies of mothers given iodine in the last trimester of pregnancy should have a cord blood sample taken at birth so that the TSH and T4 levels can be measured.

Supply and administration

Potassium iodate tablets are held in a range of specifically approved locations in the United Kingdom (such as schools and police stations) in all areas close to a nuclear installation. Hospital pharmacies have been advised to maintain a stock of potassium iodate crystals. These can be freshly dissolved when required to give the necessary 12.5 mg dose (since no pre-prepared liquid preparation of the iodate is indefinitely stable). Lugol’s iodine (a solution of 5% iodine and 10% potassium iodide) which contains 130 mg/mL of iodine is a more readily available liquid formulation of very comparable efficacy.


American Academy of Pediatrics. Committee on environmental health. Radiation disasters and children. Pediatrics 2003;111:1455–66.Find this resource:

Combet E, Bouga M, Pan B, et al. Iodine and pregnancy—a UK cross-sectional survey of dietary intake, knowledge and awareness. Br J Nutr 2015;114:108–17.Find this resource:

Connolly KJ, Pharoah POD, Hetzel BS. Fetal iodine deficiency and motor performance. Lancet 1979;ii:1149–51. [RCT]Find this resource:

de Benoist B, Andersson M, Takkouche B, et al. Prevalence of iodine deficiency worldwide. Lancet 2003;362:1859–60.Find this resource:

Department of Health. Nuclear accident countermeasures: iodine prophylaxis. Report on Health and Social Subjects No 39. London: HMSO, 1991.Find this resource:

Farebrother J, Naude CE, Nicol L, et al. Iodised salt and iodine supplements for prenatal and postnatal growth: a rapid scoping of existing systematic reviews. Nutr J 2015;14:89.[SR]Find this resource:

Farebrother J, Naude CE, Nicol L, et al. Systematic review of the effects of iodised salt and iodine supplements on prenatal and postnatal growth: study protocol. BMJ Open 2015;5:e007238.Find this resource:

Ibrahim M, Morreale de Escobar G, Visser TJ, et al. Iodine deficiency associated with parenteral nutrition in extreme preterm infants. Arch Dis Child Fetal Neonatal Ed 2003;88:F56–7.Find this resource:

Weiss W. Chernobyl thyroid cancer: 30 years of follow-up overview. Radiat Prot Dosimetry 2018;182:58–61.Find this resource:

See also the relevant Cochrane reviews

Abe SK, Balogun OO, Ota E, Takahashi K, Mori R. Supplementation with multiple micronutrients for breastfeeding women for improving outcomes for the mother and baby. Cochrane Database Syst Rev 2016;2:CD010647. Available at: this resource:

Harding KB, Peña-Rosas JP, Webster AC, et al. Iodine supplementation for women during the preconception, pregnancy and postpartum period. Cochrane Database Syst Rev 2017;3:CD011761. Available at: this resource:

Ibrahim M, Sinn J, McGuire W. Iodine supplementation for the prevention of mortality and adverse neurodevelopmental outcomes in preterm infants. Cochrane Database Syst Rev 2006;2:CD005253. Available at: this resource:

Procaine benzylpenicillin = Procaine penicillin (former BAN)


Procaine benzylpenicillin has been, for many years, the antibiotic used to treat congenital syphilis, but benzylpenicillin (q.v.), if given diligently, is now known to be just as effective.


Procaine benzylpenicillin is a sustained release drug that is slowly hydrolysed to benzylpenicillin after deep intramuscular injection. Its microbiological properties are the same as those of benzylpenicillin. Benzathine penicillin (which is even more slowly hydrolysed to benzylpenicillin over two to three weeks) was once widely used to treat syphilis in pregnancy, but it is no longer available in the United Kingdom. Luckily, the Treponema pallidum organism still remains totally sensitive to benzylpenicillin despite more than 60 years of near-universal use.

Congenital syphilis

Latent untreated maternal syphilis is associated with a 20% risk of fetal loss and a 20% risk of premature delivery, even if maternal infection has only been present for one to two years. Intra-uterine growth retardation is common. The placenta is often large, and fetal hydrops may develop. Half the liveborn babies will have congenital syphilis at birth. The longer the maternal disease has been left untreated, the greater the risk to the fetus. Florid neonatal disease is now rare, but babies can present with hepatosplenomegaly, anaemia, thrombocytopenia, jaundice, and generalized lymphadenopathy. Skin desquamation is a characteristic feature, as is a typical pink maculopapular rash that later turns brown. Osteitis is usually asymptomatic at birth, and rhinitis (‘snuffles’) only develops after a few weeks.

Syphilis is starting to become more common in the United Kingdom, and some women currently escape diagnosis and treatment before delivery. It still remains very common in some countries. A non-treponemal serological test—a Venereal Disease Research Laboratory (VDRL) or rapid plasma-reagin (RPR) test—is usually used to make the diagnosis, and false positive tests identified, if facilities exist, by undertaking a fluorescent treponemal antibody absorption (FTA-ABS), or T pallidum particle agglutination (TPPA), test.

Antenatal treatment was traditionally a single 1.8 gram (2.4 million unit) intramuscular dose of benzathine penicillin, but long-standing infection requires at least three doses at weekly intervals. A single 2 g oral dose of azithromycin (q.v.) seems as effective as one intramuscular dose of benzathine penicillin. However, most genitourinary specialists in the United Kingdom now give a 3 gram dose of benzylpenicillin intravenously or intramuscularly once every four hours for 10–14 days. Check for other sexually transmitted infections, including HIV, and review all sexual contacts.

If the mother was fully treated at least one month before delivery, as demonstrated by at least a four-titre fall in a serological non-treponemal (VDRL or RPR) test, and the baby seems asymptomatic at birth, neonatal treatment is not called for. Follow-up is, however, essential at 3, 6, and 12 months to ensure that all the serological tests eventually become negative. If there is any doubt about the adequacy of treatment, or this was only started in the second half of pregnancy, it is probably wise to x-ray the baby’s long bones for osteitis and to do a VDRL test on the cerebrospinal fluid (CSF) (also looking at the cell count and protein level). Treat any possible infection after birth like proven infection. It may also be appropriate to screen siblings for latent syphilis.


In babies thought to be infected at birth it was once traditional to give 50 mg/kg of procaine benzylpenicillin intramuscularly once a day for ten days. However, this can easily cause a sterile abscess with subsequent fibrosis and muscle atrophy, and 30 mg/kg of benzylpenicillin intravenously (or intramuscularly) once every 12 hours for 10 days is equally effective (and penetrates the CSF rather better).

If syphilis is only first suspected when the baby is already more than two weeks old then, if benzylpenicillin is to be used, it needs to be given once every six hours. While asymptomatic babies born to mothers with evidence of untreated syphilis are often given a single 100 mg/kg dose of intramuscular procaine benzylpenicillin at birth in many resource poor countries, further study may show oral azithromycin to be a useful second option as long as the community prevalence of azithromycin-resistant T pallidum is low.


Procaine benzylpenicillin acts by slowly releasing benzylpenicillin from an intramuscular depot. It should never be given intravenously. It is supplied in the United Kingdom via specialist importers as a suspension in ready-to-use 600,000 unit (1 mL), and 1.2 million unit (2 mL), cartridges, which need to be stored at 4 ºC. In many countries it is still provided as a powder, for reconstitution with water, in 1 g (1 million unit) vials that are stable at room temperature.


Chakraborty R, Luck S. Syphilis is on the increase: the implications for child health. Arch Dis Child 2008;93:105–9.Find this resource:

Nathan L, Bawdon RE, Sidawi JE, et al. Penicillin levels following the administration of benzathine penicillin G in pregnancy. Obstet Gynecol 1993;82:338–42.Find this resource:

Paryani SG, Vaughn AJ, Crosby M, et al. Treatment of asymptomatic congenital syphilis: benzathine versus procaine penicillin G therapy. J Pediatr 1994;125:471–5. [RCT]Find this resource:

Rieder G, Rusizoka M, Todd J, et al. Single-dose azithromycin versus penicillin G benzathine for the treatment of early syphilis. N Engl J Med 2005;353:1236–44. [RCT] (See also 1291–3.)Find this resource:

Simms I, Tookey PA, Goh BT, et al. The incidence of congenital syphilis in the United Kingdom: February 2010 to January 2015. BJOG 2017;124:72–7.Find this resource:

Taylor M, Gliddon H, Nurse-Findlay S, et al. Revisiting strategies to eliminate mother-to-child transmission of syphilis. Lancet Glob Health 2018;6:e26–8.Find this resource:

Townsend CL, Francis K, Peckham CS, Tookey PA. Syphilis screening in pregnancy in the United Kingdom, 2010-2011: a national surveillance study. BJOG 2017;124:79–86.Find this resource:

Wijesooriya NS, Rochat RW, Kamb ML, et al. Global burden of maternal and congenital syphilis in 2008 and 2012: a health systems modelling study. Lancet Glob Health 2016;4:e525–33.Find this resource:

See also the relevant Cochrane reviews

Shahrook S, Mori R, Ochirbat T, Gomi H. Strategies of testing for syphilis during pregnancy. Cochrane Database Syst Rev 2014;10:CD010385. Available at: this resource:

Walker GJ. Antibiotics for syphilis diagnosed during pregnancy. Cochrane Database Syst Rev 2001;3:CD001143. Available at: this resource:

See also the relevant guidelines on managing syphilis during pregnancy

Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines—2015. Available at: this resource:

Kingston M, French P, Higgins S, et al. UK national guidelines on the management of syphilis 2015. Int J STD AIDS 2016;27:421–46. Available at: this resource:

Kingston M, French P, Fifer H, et al. Congenital syphilis in England and amendments to the BASHH guideline for management of affected infants. Int J STD AIDS 2017;28:1361–2.Find this resource:



Theophylline (given intravenously as aminophylline) is a useful bronchodilator. Use as a respiratory stimulant, however, has largely been supplanted by caffeine citrate (q.v.) which has a wider therapeutic range.


Theophylline, a naturally occurring alkaloid present in tea and coffee, was widely used in the treatment of asthma for more than 50 years. The optimum bronchodilator effect is only seen with a plasma level of 10–20 mg/L, but toxic symptoms are sometimes seen in the newborn when the level exceeds 14 mg/L, and gastro-oesophageal reflux may be made worse. Sustained use increases urinary calcium loss. Very high blood levels cause hyperactivity, tachycardia, and fits that seem to respond to the oral administration of activated charcoal even when the drug has been given intravenously. Correct any hypokalaemia or metabolic acidosis. Arrhythmias that fail to respond to adenosine (q.v.) may respond to propranolol (q.v.). A single prophylactic 5 mg/kg dose given intravenously seems to reduce some of the adverse renal consequences of perinatal asphyxia.

Theophylline is moderately well absorbed in the neonate when given orally, it is extensively (up to 70%), but slowly metabolized by a series of parallel liver pathways some of which are saturable. The neonatal half-life (15–50 hours) is five times as long as in adults.

Caffeine has many advantages over theophylline in the management of neonatal apnoea. The gap between the optimum therapeutic blood level and the blood level at which toxic symptoms first appear is much wider with caffeine than it is with theophylline, and caffeine usually only needs to be given once a day. Theophylline is, in any case, partly metabolized by methylation to caffeine in the liver in the neonatal period.

Unlike caffeine citrate, which has now widely come to be used for its neuro-developmentally protective effects, aminophylline does not seem to share the same beneficial effects.

Fetal and infant implications of maternal treatment

Theophylline crosses the placenta (F:M ratio 1.0). In rodent studies at normal doses it does not appear to cause teratogenicity but in high doses it causes fetal toxicity, cleft palate, and skeletal malformations. None of the studies in human pregnancy have found any adverse fetal effects.

Theophylline enters breastmilk. It may cause irritability in the breastfed newborn. Despite the long half-life at this age toxicity in the breastfed infant is rare. Women who choose to breastfeed should monitor their baby’s behaviour closely.

Drug interactions

Toxicity can occur in patients also taking cimetidine, ciprofloxacin, erythromycin, or isoniazid unless a lower dose of theophylline is used. Conversely, a higher dose may be needed in patients on carbamazepine, phenobarbital, phenytoin, or rifampicin because of enhanced drug clearance. Treatment with theophylline, in turn, may make it necessary to increase the dose of phenytoin.

Drug equivalence

Aminophylline (which includes ethylenediamine in order to improve solubility) is only 85% theophylline but there is a suggestion that neonatal bioavailability is reduced by first-pass liver metabolism, and that the dose of theophylline used for oral treatment can be the same as the dose of aminophylline given intravenously.


Intravenous treatment for the preterm baby:

Try 8 mg/kg of aminophylline as a loading dose over not less than ten minutes followed by 2.5 mg/kg (or, if necessary, 3.5 mg/kg) once every 12 hours. Because of the long half-life, a continuous infusion is not necessary. A rapid intravenous bolus injection can cause arrhythmia.

Oral treatment for the preterm baby:

Try an initial loading dose of 6 mg/kg of theophylline (if the patient is not already on intravenous treatment) followed by 2.5 mg/kg every 12 hours.

Use in older children:

To start oral treatment in babies aged 1–11 months calculate the total daily dose of theophylline required per kg body weight as 5 mg plus 0.2 times the child’s postnatal age in weeks.

Blood levels

The optimum plasma level in neonates is probably 9–14 mg/L (1 mg/L = 5.55 micromol/L). Significant side effects can appear when the level exceeds 15 mg/L in the newborn baby, and when the level exceeds 20 mg/L (100 micromol/L) in older children, the difference probably being due to differences in protein binding. Timing is not crucial because of the long neonatal half-life, but specimens are best collected an hour after administration.


One 10 mL ampoule containing 250 mg of aminophylline costs 65p.


Askenazi D. Should neonates with perinatal asphyxia receive a single dose of IV theophylline to prevent acute kidney injury? Acta Paediatr 2016;105:1125–6.Find this resource:

Bakr AF. Prophylactic theophylline to prevent renal dysfunction in newborns exposed to perinatal asphyxia—a study in a developing country. Pediatr Nephrol 2005;20:1249–52.Find this resource:

Bhat MA, Shah ZA, Makhdoomi MS, et al. Theophylline for renal function in term neonates with perinatal asphyxia: a randomized, placebo-controlled trial. J Pediatr 2006;149:180–4. [RCT]Find this resource:

Hogue SL, Phelps SJ. Evaluation of three theophylline dosing equations for use in infants up to one year of age. J Pediatr 1993;123:651–6.Find this resource:

Khurana S, Shivakumar M, Sujith Kumar Reddy GV, et al. Long-term neurodevelopment outcome of caffeine versus aminophylline therapy for apnea of prematurity. J Neonatal Perinatal Med 2017;10:355–62. [RCT]Find this resource:

Lowry JA, Jarrett RV, Wasserman G, et al. Theophylline toxicokinetics in premature newborns. Arch Pediatr Adolesc Med 2001;155:934–9.Find this resource:

Maeda T, Inoue M, Sekiguchi K, et al. Aminophylline-associated irritable behaviour in preterm neonates. Early Hum Dev 2016;99:37–41.Find this resource:

Raina A, Pandita A, Harish R, et al. Treating perinatal asphyxia with theophylline at birth helps to reduce the severity of renal dysfunction in term neonates. Acta Paediatr 2016;105:e448–51. [RCT]Find this resource:

Rocklin RE. Asthma, asthma medications and their effects on maternal/fetal outcomes during pregnancy. Reprod Toxicol 2011;32:189–97.Find this resource:

Tey SL, Lee WT, Lee PL, et al. Neurodevelopmental outcomes in very low birth weight infants using aminophylline for the treatment of apnea. Pediatr Neonatol 2016;57:41–6. (See also: Liao SL. Insights into aminophylline and neurodevelopmental outcome in premature infants. Pediatr Neonatol 2016;57:1–2; And Shen CM. Aminophylline therapy and the neurodevelopment in premature infants. Pediatr Neonatol 2016;57:3–4.)Find this resource:

See also the relevant Cochrane reviews

Ng G, da Silva O, Ohlsson A. Bronchodilators for the prevention and treatment of chronic lung disease in preterm infants. Cochrane Database Syst Rev 2016;12:CD003214. Available at: this resource:

Henderson-Smart DJ, De Paoli AG. Prophylactic methylxanthine for prevention of apnoea in preterm infants. Cochrane Database Syst Rev 2010;12:CD000432. Available at: this resource:

Henderson-Smart DJ, De Paoli AG. Methylxanthine treatment for apnoea in preterm infants. Cochrane Database Syst Rev 2010;12:CD000140. Available at: this resource:

Henderson-Smart DJ, Davis PG. Prophylactic methylxanthines for endotracheal extubation in preterm infants. Cochrane Database Syst Rev 2010;12:CD000139. Available at: this resource:

Tin-mesoporphyrin = Stannsoporfin


Tin-protoporphyrin and tin-mesoporphyrin have been used in the management of porphyria. They were also used experimentally for some 15 years from 1989 to inhibit bilirubin production in the neonatal period.


Phenobarbital (q.v.) was the first drug used both antenatally and after birth to prevent potentially dangerous levels of jaundice developing in the neonatal period. Phenobarbital works by inducing liver enzyme activity and enhancing bilirubin excretion. The use of a specific enzyme inhibitor to decrease the rate at which haem is degraded to bilirubin as a result of red cell destruction provides an alternative strategy in the management of neonatal jaundice. A range of tin-porphyrins have been shown to inhibit the activity of haem oxygenase, the rate-limiting enzyme in this process. Tin-protoporphyrin was used in most early studies, but tin-mesoporphyrin has been shown to be a particularly potent inhibitor of bilirubin production, and this is the product that has been used in all the most recent studies into the management of jaundice. Following experience of short-term use (1 micromol/kg intravenously every other day) in older children with uncontrolled jaundice due to Type 1 Crigler–Najjar syndrome, it has now been used experimentally to reduce peak bilirubin levels in babies at serious risk of significant neonatal jaundice.

Evidence that tin-mesoporphryin can prevent jaundice when given early does not, however, mean that it will necessarily prove of much value in the management of babies who have already become seriously jaundiced unless jaundice is likely to be prolonged. Neither should the use of this still experimental drug be encouraged in most clinical settings merely in order to reduce the need for phototherapy until as much is known about the safety of this drug as is known about the safety of phototherapy. Exchange transfusion and possibly immunoglobulins will likely remain central to the initial management of haemolytic disease in babies born to mothers with anti-c, anti-D, and anti-Kell antibodies (including the correction of severe anaemia at birth). The drug may eventually come to have a place however, if given early, in the management of several of the conditions capable of causing dangerous neonatal jaundice.

When treatment is sustained the drug seems to have an effect on intestinal haem oxidase, reducing iron absorption and causing a mild iron-deficiency anaemia after about two months unless further supplemental oral iron is given. Inhibiting bilirubin production does not cause haem to accumulate, because of a compensatory increase in haem excretion through the biliary tract.


All studies to date have been exploratory and experimental. However, a single dose of 6 micromol/kg of tin-mesoporphyrin intramuscularly shortly after birth seemed to be capable of reducing neonatal jaundice in the preterm baby by at least 40%. It might therefore be particularly useful in facilitating safe early post-delivery discharge in a number of conditions (such as ABO incompatibility and G6PD deficiency) that sometimes cause dangerous late neonatal jaundice but which do not normally also cause serious anaemia.


Vials containing 24 micromol/mL of tin-mesoporphyrin were used in the recently reported neonatal studies. Vials kept in the dark and stored at 4 ºC are stable for up to one year. The product is given intramuscularly (or intravenously where the volume involved makes this necessary).


Bhutani VK, Poland R, Meloy LD, et al. Clinical trial of tin mesoporphyrin to prevent neonatal hyperbilirubinemia. J Perinatol 2016;36:533–9. [RCT]Find this resource:

Dover SB, Graham A, Fitzsimons E, et al. Haem arginate plus tin-protoporphyrin for acute hepatic porphyria. Lancet 1991;338:263.Find this resource:

Galbraith RA, Drummond GS, Kappas A. Suppression of bilirubin production in the Criggler Najjar type 1 syndrome: studies with the heme oxygenase inhibitor tin-mesoporphyrin. Pediatrics 1992;89:175–82.Find this resource:

Kappas A. A method for interdicting the development of severe jaundice in newborns by inhibiting the production of bilirubin. Pediatrics 2004;113:119–23 (see also 134–5).Find this resource:

Kappas A, Drummond GS, Valaes T. A single dose of Sn-mesoporphyrin prevents development of severe hyperbilirubinemia in Glucose-6-phosphate dehydrogenase-deficient newborns. Pediatrics 2001;108:25–30.Find this resource:

Martinez JC, Garcia HO, Otheguy LE, et al. Control of severe hyperbilirubinemia in full-term newborns with the inhibitor of bilirubin production Sn-mesoporphyrin. Pediatrics 1999;103:1–5. [RCT]Find this resource:

Schulz S, Wong RJ, Vremanand HJ, et al. Metalloporphyrins—an update. Front Pharmacol 2012;3:68.Find this resource:

Stevenson DK, Wong RJ. Metalloporphyrins in the management of neonatal hyperbilirubinemia. Semin Fetal Neonatal Med 2010;15:164–8.Find this resource:

Valaes T, Petmezaki S, Henschke C, et al. Control of jaundice in preterm newborns by an inhibitor of bilirubin production: studies with tin-mesoporphyrin. Pediatrics 1994;93:1–11. [RCT]Find this resource:

Valaes TN, Harvey-Wilkes K. Pharmacologic approaches to the prevention and treatment of neonatal hyperbilirubinaemia. Clin Perinatol 1990;17:245–73.Find this resource:

See also the relevant Cochrane review

Suresh GK, Martin CL, Soll RF. Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates. Cochrane Database Syst Rev 2003;2:CD004207. Available at: this resource:



Tolazoline was, prior to the introduction of inhaled nitric oxide (q.v.), frequently used to treat persistent pulmonary hypertension (PPHN) after birth.


Tolazoline is an α‎-adrenergic antagonist that produces both pulmonary and systemic vasodilatation. The first paper to describe neonatal use appeared in 1979. Several papers then reported the drug’s ability to improve systemic arterial oxygen tension in some critically ill babies with a transitional circulation, especially where there is clear evidence of pulmonary hypertension. Anecdotal evidence suggests that the drug works best once serious acidosis (pH < 7.2) is corrected.

Continuous infusion is not nearly as necessary as was once thought, because the half-life exceeds six hours. Babies given a continuous tolazoline infusion must have their blood pressure measured periodically (or better yet, continuously), but systemic hypotension should be rare with the dose recommended here. Many texts have recommended higher doses and sustained treatment but this can be cardiotoxic, and, since tolazoline is actively excreted by the kidney but not otherwise metabolized by the baby, such problems will be exacerbated by renal failure. Other side effects of tolazoline include sympathomimetic cardiac stimulation, parasympathomimetic gastrointestinal symptoms, and increased gastric secretion due to a histamine-like action. The skin may take on an alarmingly blotchy appearance from histamine release. Transient oliguria and gastric bleeding have been reported.

Tolazoline may also be given by inhalation, sometimes while inhaled nitric oxide is being prepared. Direct administration into the lungs certainly makes systemic side effects less likely, and there are now several reports that this strategy can be successful.

Drug interactions

The use of an H2 blocker such as ranitidine (q.v.) prophylactically to minimize the risk of gastric bleeding, renders tolazoline ineffective as a vasodilator.


Correction of pulmonary hypertension (intravenous route):

Give 0.5–1 mg/kg intravenously over two to four minutes while watching for systemic hypotension. It is just occasionally necessary to sustain this by giving 100–200 microgram/kg per hour intravenously diluted in a 0.9% sodium chloride or 10% glucose. Doses above 300 micrograms/kg per hour have been associated with cardiotoxicity and renal failure.

Endotracheal administration:

Try 1 mg/kg diluted in 0.5 mL of 0.9% sodium chloride.

Use to correct arterial vasospasm:

Low-dose infusion (even as little as 20, but more usually 100, microgram/kg per hour) will often correct the local vasospasm triggered by an indwelling arterial line.


Tolazoline can be added (terminally) into a line containing dobutamine and/or dopamine or vancomycin. One book has an unreferenced claim that it can be added to total parenteral nutrition (TPN). Do not add to a line containing lipid.


1 mL ampoules containing 25 mg of tolazoline are available from ‘special-order’ manufacturers or specialist importing companies. Prepare a fresh solution daily.


Bush A, Busst CM, Knight WB, et al. Cardiovascular effects of tolazoline and ranitidine. Arch Dis Child 1987;62:241–6.Find this resource:

Dhillon R. The management of neonatal pulmonary hypertension. Arch Dis Child Fetal Neonatal Ed 2012;97:F223–8.Find this resource:

Lemke RP, al Saedi SA, Belik J, et al. Use of tolazoline to counteract vasospasm in peripheral arterial catheters in neonates. Acta Paediatr 1996;85:1497–8.Find this resource:

Nuntnarumit P, Korones SB, Yang W, et al. Efficacy and safety of tolazoline for treatment of severe hypoxemia in extremely preterm infants. Pediatrics 2002;109:852–6 (see also Yurdakök M. J Perinatol 1998;18:423).Find this resource:

Parida SK, Baker S, Kuhn R, et al. Endotracheal tolazoline administration in neonates with persistent pulmonary hypertension. J Perinatol 1997;17:461–4.Find this resource:

Ward RM. Pharmacology of tolazoline. Clin Perinatol 1984;11:703–13.Find this resource:

Ward RM, Daniel CH, Kendig JW. Oliguria and tolazoline pharmacokinetics in the newborn. Pediatrics 1986;77:307–15.Find this resource:



Vecuronium was used as an alternative to pancuronium (q.v.) and can be used to provide sustained muscle paralysis. Atracurium (q.v.) and suxamethonium (q.v.) are better alternatives where only short-term paralysis is required and are more suited to use during intubation. Manufacturing of the drug ceased in 2015.


Vecuronium bromide is a competitive non-depolarizing muscle relaxant that came onto the market in 1980, as an alternative to pancuronium. The duration of action is not as long as that provided by a comparable dose of pancuronium. Vecuronium is slightly more expensive, but generates less histamine release, and produces few or no adverse cardiovascular effects. It is rapidly taken up by the liver and partially metabolized prior to excretion, largely in the bile. Some of the metabolites, such as 3-desacetyl-vecuronium, which retain considerable neuromuscular blocking activity, are mostly excreted in the urine.

The normal plasma elimination half-life in adults is 30–60 minutes, but considerably (and sometimes unpredictably) longer than this in infancy, especially when high-dose treatment is used. Table B2 shows the comparative time to onset and duration of action for muscle relaxants used in infants.

Table B2 Onset and duration of action


Onset of action

Duration of action after initial dose


2–3 minutes

20–35 minutes


1.5–2 minutes

20–35 minutes


1–2 minute

10–15 minutes


2–3 minutes

60–100 minutes


1–2 minutes

22–67 minutes (dose dependent)


0.5–1 minutes

4–6 minutes


2.5–3 minutes

20–40 minutes

Renal failure seems to have relatively little clinical effect on the duration of neuromuscular blockade, but 25% of the drug is renally excreted and atracurium may be the best drug to use in a baby with severe renal failure requiring paralysis. Concurrent treatment with an aminoglycoside or magnesium sulfate may extend the duration of neuromuscular blockade. Use of infusions of vecuronium carry a significant risk of drug accumulation and are best avoided.

Use during neonatal therapeutic hypothermia

Therapeutic hypothermia reduces plasma clearance of vecuronium by about 11% for each degree Celsius reduction in core temperature and as a result the action of vecuronium is prolonged compared to that seen in normothermia.

Fetal and infant implications of maternal treatment

Placental transfer is limited, and doses of up to 100 micrograms/kg given to mothers requiring caesarean delivery seem to have no significant clinical effect on the baby.


First dose: 100 micrograms/kg by intravenous injection will cause respiratory paralysis.

Further doses: The standard repeat dose is 30–50 microgram per kilogram intravenously every two to four hours as necessary, but some larger and older babies seem to require a higher maintenance dose (up to 150 micrograms has been used). Babies who are paralyzed should always be sedated as well.

Infusion: vecuronium may be given as an infusion at a rate of 0.8–1.4 microgram/kg/minute however due to the risks of accumulation infusions carry a significant risk of prolonged paralysis and muscle weakness long after the drug has been stopped.


Most of the effects of vecuronium can be reversed by giving a combination of 10 micrograms/kg of glycopyrronium (or 20 micrograms/kg of atropine), and 50 micrograms/kg of neostigmine.


Vecuronium comes as a powder in 10 mg vials, with water for reconstitution. Dissolve the powder with 5 mL of sterile water (as supplied) to give a solution containing 2 mg/mL. Vials can, if necessary, be kept for up to 24 hours after reconstitution but, because they contain no preservative, any drug not used promptly is best discarded.

For single doses: further dilute 0.5 mL of this solution with 0.5 mL of 0.9% sodium chloride or 5% dextrose in a 1 mL syringe to obtain a preparation containing 100 micrograms in 0.1 mL for accurate neonatal administration.

For infusion: take 2.5 mL (5 mg) of the reconstituted solution for each kg body weight and dilute to a final volume of 50 mL with glucose 5% or sodium chloride 0.9%. Running this solution at a rate of 0.5 mL/hour provides a dose of 50 microgram/kg/hour (0.83 microgram /kg/minute); running the solution at a rate of 0.8 mL/hour provides a dose of 80 microgram/kg/hour (which approximates the upper dose of 1.33 microgram/kg/minute).


Björklund LJ. Use of sedatives and muscle relaxants in newborn babies receiving mechanical ventilation. Arch Dis Child 1993;69:544.Find this resource:

Gravlee GP, Ramsey FM, Roy RC, et al. Rapid administration of a narcotic and neuromuscular blocker: a haemodynamic comparison of fentanyl, sufentanil, pancuronium and vecuronium. Anesth Analg 1988;67:39–47.Find this resource:

Martin LD, Bratton SL, O’Rourke P. Clinical uses and controversies of neuromuscular blocking agents in infants and children. Crit Care Med 1999;27:1358–68.Find this resource:

Meretoja OA, Wirtavouri K, Neuvonen PJ. Age-dependence of the dose-response curve of vecuronium in pediatric patients during balanced anesthesia. Anesth Analg 1988;67:21–6.Find this resource:

Playfor S. Neuromuscular blocking agents in critically ill children. Paediat Perinat Drug Ther 2002;5:35–46.Find this resource:

Scheiber G, Ribeiro FC, Marichal A, et al. Intubating conditions and onset of action after rocuronium, vecuronium, and atracurium in young children. Anesth Analg 1996;83:320–4.Find this resource:

Sparr HJ, Beuafort TM, Fuchs-Buder T. Newer neuromuscular blocking agents. How do they compare with established agents? Drugs 2001;61:919–42.Find this resource:

Caldwell JE, Heier T, Wright PM, et al. Temperature-dependent pharmacokinetics and pharmacodynamics of vecuronium. Anesthesiology 2000;92:84–93.Find this resource:

Withington D, Menard G, Harris J, et al. Vecuronium pharmacokinetics and pharmacodynamics during hypothermic cardiopulmonary bypass in infants and children. Can J Anaesth 2000;47:1188–95.Find this resource: