2 Cardiovascular system
2.1 Positive inotropic drugs
2.1.1 Cardiac glycosides 2.1.2 Phosphodiesterase inhibitors
Positive inotropic drugs increase the force of contraction of the myocardium.
Drugs which produce inotropic effects include cardiac glycosides, phosphodi-esterase inhibitors, and some sympathomimetics (section 2.7.1).
2.1.1
Cardiac glycosidesThe cardiac glycoside digoxin increases the force of myocardial contraction and reduces conductivity within the atrioventricular (AV) node.
Digoxin is most useful in the treatment of supraventricular tachycardias, espe-cially for controlling ventricular response in persistent atrial fibrillation (section 2.3.1). Digoxin has a limited role in children with chronic heart failure; for reference to the role of digoxin in heart failure, see section 2.2.
For the management of atrial fibrillation, the maintenance dose of digoxin is determined on the basis of the ventricular rate at rest, which should not be allowed to fall below an acceptable level for the child.
Digoxin is now rarely used for rapid control of heart rate (see section 2.3.2), even with intravenous administration, response may take many hours; persistence of tachycardia is therefore not an indication for exceeding the recommended dose.
The intramuscular route isnot recommended.
Unwanted effects depend both on the concentration of digoxin in the plasma and on the sensitivity of the conducting system or of the myocardium, which is often increased in heart disease. It can sometimes be difficult to distinguish between toxic effects and clinical deterioration because the symptoms of both are similar.
Also, the plasma-digoxin concentration alone cannot indicate toxicity reliably but the likelihood of toxicity increases progressively through the range 1.5 to 3 micr-ograms/litre for digoxin. Renal function is very important in determining digoxin dosage.
Hypokalaemia predisposes the child to digitalis toxicity and should be avoided; it is managed by giving a potassium-sparing diuretic or, if necessary, potassium supplements (or foods rich in potassium).
Toxicity can often be managed by discontinuing digoxin and correcting hypokal-aemia if appropriate; serious manifestations require urgent specialist manage-ment.Digoxin-specific antibody fragments are available for reversal of life-threatening overdosage (see below).
DIGOXIN
Cautions sick sinus syndrome; thyroid disease;
hypoxia; severe respiratory disease; avoid hypo-kalaemia, hypomagnesaemia, hypercalcaemia, and hypoxia (risk of digitalis toxicity); monitor serum electrolytes and renal function; avoid rapid intravenous administration (risk of hypertension and reduced coronary flow);interactions:
Appendix 1 (cardiac glycosides) Renal impairment reduce dose; toxicity increased by electrolyte disturbances, adjust dose according to plasma-digoxin concentration Pregnancy may need dosage adjustment Breast-feeding amount too small to be harmful
Contra-indications intermittent complete heart block, second degree AV block; supraventricular arrhythmias associated with accessory conduct-ing pathways e.g. Wolff-Parkinson-White syndrome (although can be used in infancy);
ventricular tachycardia or fibrillation; hyper-trophic cardiomyopathy (unless concomitant atrial fibrillation and heart failure—but with cau-tion); myocarditis; constrictive pericarditis (unless to control atrial fibrillation or improve systolic dysfunction—but use with caution) Side-effects see notes above; also nausea,
vomi-ting, diarrhoea; arrhythmias, conduction distur-bances; dizziness; blurred or yellow vision; rash,
BNFC 2009 2.1 Positive inotropic drugs
97
2Cardiovascularsystem
eosinophilia; less commonly depression; very rarely anorexia, intestinal ischaemia and necrosis, psy-chosis, apathy, confusion, headache, fatigue, weakness, gynaecomastia on long-term use, and thrombocytopenia
Pharmacokinetics For plasma-digoxin concen-tration assay, blood should ideally be taken at least 6 hours after a dose; plasma-digoxin con-centration should be maintained in the range 0.8–
2 micrograms/litre (see also notes above) Licensed use heart failure, supraventricular
arrhythmias Indication and dose
Supraventricular arrhythmias and chronic heart failure (see also notes above)consult product literature for details
. By mouth
Neonate under 1.5 kginitially 25 micrograms/
kg in 3 divided doses for 24 hours then 4–
6 micrograms/kg daily in 1–2 divided doses Neonate 1.5–2.5 kginitially 30 micrograms/kg in 3 divided doses for 24 hours then 4–6 micr-ograms/kg daily in 1–2 divided doses Neonate over 2.5 kginitially 45 micrograms/kg in 3 divided doses for 24 hours then 10 micr-ograms/kg daily in 1–2 divided doses Child 1 month–2 yearsinitially 45 micrograms/
kg in 3 divided doses for 24 hours then 10 micrograms/kg daily in 1–2 divided doses Child 2–5 yearsinitially 35 micrograms/kg in 3 divided doses for 24 hours then 10 micrograms/
kg daily in 1–2 divided doses
Child 5–10 yearsinitially 25 micrograms/kg (max. 750 micrograms) in 3 divided doses for 24 hours then 6 micrograms/kg daily (max.
250 micrograms daily) in 1–2 divided doses Child 10–18 yearsinitially 0.75–1.5 mg in 3 divided doses for 24 hours then 62.5–250 micr-ograms daily in 1–2 divided doses (higher doses may be necessary)
. By intravenous infusion (but rarely necessary) Neonate under 1.5 kginitially 20 micrograms/
kg in 3 divided doses for 24 hours then 4–
6 micrograms/kg daily in 1–2 divided doses Neonate 1.5–2.5 kginitially 30 micrograms/kg in 3 divided doses for 24 hours then 4–6 micr-ograms/kg daily in 1–2 divided doses Neonate over 2.5 kginitially 35 micrograms/kg in 3 divided doses for 24 hours then 10 micr-ograms/kg daily in 1–2 divided doses Child 1 month–2 yearsinitially 35 micrograms/
kg in 3 divided doses for 24 hours then 10 micrograms/kg daily in 1–2 divided doses
Child 2–5 yearsinitially 35 micrograms/kg in 3 divided doses for 24 hours then 10 micrograms/
kg daily in 1–2 divided doses
Child 5–10 yearsinitially 25 micrograms/kg (max. 500 micrograms) in 3 divided doses for 24 hours then 6 micrograms/kg daily (max.
250 micrograms daily) in 1–2 divided doses Child 10–18 yearsinitially 0.5–1 mg in 3 divided doses for 24 hours then 62.5–250 micrograms daily in 1–2 divided doses (higher doses may be necessary)
Less urgent digitalisation . By mouth
Rapid digitalisation may not always be required.
Child 10–18 years250–500 micrograms daily (higher dose may be divided) for 5–7 days fol-lowed by maintenance dose
NoteThe above doses may need to be reduced if digoxin (or another cardiac glycoside) has been given in the preceding 2 weeks. When switching from intravenous to oral route may need to increase dose by 20–30% to maintain the same plasma digoxin concentration. Plasma monitoring may be required when changing formulation to take account of varying bioavailabilities. For plasma concentration monitoring, blood should ideally be taken at least 6 hours after a dose
Administration For intravenous infusion, dilute with sodium chloride 0.9% intravenous infusion or glucose 5% to a max. concentration of 62.5 micrograms/mL; loading doses should be given over 30–60 minutes and maintenance dose over 10–20 minutes. Protect from light.
For oral administration, oral solution mustnot be diluted
Digoxin(Non-proprietary)A
Tablets, digoxin 62.5 micrograms, net price 28 =
£1.66; 125 micrograms, 28 = £1.34; 250 micr-ograms, 28 = £1.37
Injection, digoxin 250 micrograms/mL, net price 2-mL amp = 70p
Excipientsinclude alcohol, propylene glycol (see excipients) Available from Antigen
Paediatric injection, digoxin 100 micrograms/mL Available from ‘special-order’ manufacturers or specialist importing companies, see p. 943
Lanoxinc(GSK)A
Tablets, digoxin 125 micrograms, net price 20 = 32p; 250 micrograms (scored), 20 = 32p Injection, digoxin 250 micrograms/mL, net price 2-mL amp = 66p
Lanoxin-PGc(GSK)A
Tablets, blue, digoxin 62.5 micrograms. Net price 20 = 32p
Elixir, yellow, digoxin 50 micrograms/mL. Do not dilute, measure with pipette. Net price 60 mL =
£5.35. Counselling, use of pipette
Digoxin-specific antibody
Digoxin-specific antibody fragments are indicated for the treatment of known or strongly suspected digoxin or digitoxin overdosage, in situations where mea-DIGOXIN (continued)
98
2.1.1 Cardiac glycosides BNFC 20092Cardiovascularsystem
sures beyond the withdrawal of the cardiac glycoside and correction of any electrolyte abnormalities are felt to be necessary (see also notes above).
Digibindc(GSK)A
Injection, powder for preparation of infusion, digoxin-specific antibody fragments (F(ab)) 38 mg.
Net price per vial = £93.97 (hosp. and poisons centres only)
Dose
Consult product literature or Poisons Information Centre
2.1.2
Phosphodiesterase inhibitorsEnoximone and milrinone are selective phosphodiesterase inhibitors which exert most of their effect on the myocardium. They possess positive inotropic and vasodilator activity and are useful in infants and children with low cardiac output especially after cardiac surgery. Phosphodiesterase inhibitors should be limited to short-term use because long-term oral administration has been asso-ciated with increased mortality in adults with congestive heart failure.
ENOXIMONE
Cautions heart failure associated with hyper-trophic cardiomyopathy, stenotic or obstructive valvular disease or other outlet obstruction;
monitor blood pressure, heart rate, ECG, central venous pressure, fluid and electrolyte status, renal function, platelet count, hepatic enzymes;
avoid extravasation;interactions: Appendix 1 (phosphodiesterase inhibitors)
Hepatic impairment dose reduction may be required
Renal impairment consider dose reduction Pregnancy manufacturer advises use only if potential benefit outweighs risk
Breast-feeding manufacturer advises caution—
no information available
Side-effects ectopic beats; less frequently ventri-cular tachycardia or supraventriventri-cular arrhythmias (more likely in children with pre-existing arrhy-thmias); hypotension; also headache, insomnia, nausea and vomiting, diarrhoea; occasionally, chills, oliguria, fever, urinary retention; upper and lower limb pain
Licensed use not licensed for use in children
Indication and dose
Congestive heart failure, low cardiac output following cardiac surgery
. By intravenous injection and continuous intra-venous infusion
Neonateinitial loading dose of 500 micr-ograms/kg by slow intravenous injection, followed by 5–20 micrograms/kg/minute by continuous intravenous infusion over 24 hours adjusted according to response; max 24 mg/kg over 24 hours
Child 1 month–18 yearsinitial loading dose of 500 micrograms/kg by slow intravenous injection, followed by 5–20 micrograms/kg/minute by continuous intravenous infusion over 24 hours adjusted according to response; max. 24 mg/kg over 24 hours
Administration for intravenous administration dilute to concentration of 2.5mg/mL with sodium chloride 0.9% intravenous infusion or water for injections; the initial loading dose should be given by slow intravenous injection over at least 15 minutes. Use plastic apparatus—crystal forma-tion if glass used
Perfanc(INCA-Pharm)A
Injection, enoximone 5 mg/mL. For dilution before use. Net price 20-mL amp = £15.02
Excipientsinclude alcohol, propylene glycol
MILRINONE
Cautions see under Enoximone; also correct hypokalaemia; monitor renal function; interac-tions: Appendix 1 (phosphodiesterase inhibitors) Renal impairment reduce dose and monitor response
Pregnancy manufacturer advises use only if potential benefit outweighs risk
Breast-feeding manufacturer advises caution—
no information available
Side-effects ectopic beats, ventricular tachy-cardia, supraventricular arrhythmias (more likely in children with pre-existing arrhythmias), hypo-tension; headache; less commonly ventricular fibrillation, chest pain, tremor, hypokalaemia,
thrombocytopenia; very rarely bronchospasm, anaphylaxis, and rash
Licensed use not licensed for use in children under 18 years
Indication and dose
Congestive heart failure, low cardiac output following cardiac surgery, shock
. By intravenous infusion
Neonateinitially 50–75 micrograms/kg over 30–60 minutes (reduce or omit initial dose if at risk of hypotension) then 30–45 micrograms/
kg/hour by continuous intravenous infusion for 2–
3 days (usually for 12 hours after cardiac sur-gery)
BNFC 2009 2.1.2 Phosphodiesterase inhibitors
99
2Cardiovascularsystem
Child 1 month–18 yearsinitially 50–75 micr-ograms/kg over 30–60 minutes (reduce or omit initial dose if at risk of hypotension) then 30–
45 micrograms/kg/hour by continuous intra-venous infusion for 2–3 days (usually for 12 hours after cardiac surgery)
Administration for intravenous infusion dilute with glucose 5% or sodium chloride 0.9% or sodium chloride and glucose intravenous infusion to a
concentration of 200 micrograms/mL (higher concentrations of 400 micrograms/mL have been used); loading dose may be given undiluted if fluid-restricted
Primacorc(Sanofi-Aventis)A
Injection, milrinone (as lactate) 1 mg/mL, net price 10-mL amp = £16.61