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ACE Inhibitors in Paediatrics

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For use in Ward 23B Intensive observation area (IOA)

How do Angiotensin Converting Enzyme inhibitors (ACE inhibitors) work?

  • By inhibiting the ACE enzyme from converting angiotensin I to angiotensin II as part of the renin-aldosterone-angiotensin pathway.
  • In heart failure, cardiac output is decreased. To adapt to this decrease in cardiac output, arterial pressure and perfusion to essential organs is maintained by increased vasoconstriction activity through the sympathetic nervous system and renin-aldosterone-angiotensin system. Angiotensin II is produced and acts as a potent vasoconstrictor and also results in cardiac remodelling (cardiac hypertrophy) in people with heart failure.

    ACE inhibitors decrease the production of angiotensin II and thereby decrease the vasoconstriction (or increased after-load) against which the left ventricle needs to pump. This results in decreased myocardial work, thus improving cardiac output.

    The body does not develop a tolerance to ACE inhibitors which make them a good choice for long-term therapy.

Indications

  1. Myocardial dysfunction
  2. Valvular regurgitation. Indicated in aortic regurgitation. ACE inhibitor use is controversial in mitral regurgitation unless there is also impaired cardiac function.
  3. Post-operative patients with heart failure.
  4. Other indications exist, but are uncommon in the Paediatric Cardiology service (see NZ Formulary for Children http://nzfchildren.org.nz/nzf_1242 for further information)

Side Effects

  • Hypotension
    Most common side effect, may occur whenever the dose is increased
    If significant (i.e. associated with symptoms) can be treated by IV fluid bolus
    If occurs with dose increase, then to go back to the lower dose
    Patients receiving concomitant diuretics at high doses (or who are volume-depleted from other causes) may be particularly at risk
  • Renal Impairment
    Uncommonly patients may develop acute renal failure
    Serum electrolytes should be monitored prior to and after initiation or dose increase
    Discontinue if renal failure occurs
  • Cough
    Persistent dry cough, seems to be dose dependant, more common with enalapril
  • Neutropenia
    Uncommon, but incidence increased in renal failure. Encourage parents to report signs of infection.
  • Hypersensitivity reactions, including angioedema.
  • Other side effects as listed in the NZ Formulary for Children (http://nzfchildren.org.nz/nzf_1242).

Caution and Monitoring

  • Should be used with caution in patients with renal failure / renal disease
  • Should be avoided in patients with "fixed output state" - i.e. patients with aortic stenosis or coarctation.
  • Monitor serum potassium (often ACE inhibitors are used in conjunction with diuretics, and ACE inhibitors may alter potassium levels themselves).
  • ACE inhibitors are potassium sparing therefore amiloride or spironolactone (and other potassium sparing agents) should usually be discontinued.
  • Monitor serum sodium: the hypotensive action of ACE inhibitors is potentiated by hyponatremia.
  • Absorption of captopril is reduced by food and it should be given on an empty stomach - give one hour before food
  • Neonatal response to ACE inhibitors is very variable, and profound hypotension may occur with even small doses. Use in this population should be avoided if possible, and any necessary use should be closely monitored.

Commonly used ACE inhibitors in paediatrics

There are numerous ACE inhibitors available; however the ACE inhibitors most commonly used (and studied) in children are:

  1. Captopril: usually the first ACE inhibitor to be used as it has a short half life. Administer every 8 hours. See dose range in Table 1 below. (click on link to access parent information sheet)

  2. Enalapril: administered twice daily. Dose range 0.05mg/kg/dose to 0.5mg/kg/dose (~0.1mg/kg/day to 1mg/kg/day). Usual target dose is 0.5mg/kg/day in two divided doses6.

  3. Cilazapril: administered once daily. Dose range 0.5mg/day - 2.5mg/day (adult max dose 5mg/day) - Note NOT per Kg. Commonly reserved for older children/adolescents

Table 1. Captopril Dosage (From NZFC: www.nzfchildren.org.nz)4
Neonates: Use with caution
Test dose: 0.01-0.05mg/kg/dose 
(0.01 mg/kg in premature infants <37weeks corrected gestational age)
Monitor blood pressure carefully for 1-2 hours; if tolerated give 0.01- 0.05 mg/kg 2-3 times daily, increased as necessary to maximum 2 mg/kg daily in divided doses (maximum 0.3mg/kg daily in divided doses in neonate < 37 weeks corrected gestational age)
Child 1 month - 12 years:
Test dose: 0.1mg/kg (maximum 6.25mg)
Monitor blood pressure carefully for 1-2 hours; if tolerated give 0.1 - 0.3mg/kg 2-3 times a day. Usual target dose 1mg/kg/dose TDS6
Can be increased as necessary to maximum 6 mg/kg daily in divided doses (maximum 4 mg/kg daily in divided doses for child 1 month -1 year)
Child 12 - 18 years:
Test dose: 0.1mg/kg or 6.25mg.
Monitor blood pressure carefully for 1-2 hours; if tolerated give 12.5-25 mg 2-3 times a day, increased as necessary to maximum 150 mg daily in divided doses 

Inpatients: initiation and titration of Captopril for children > one month of age

For Neonates - dose regimen see Table 1 above.

Commencing an ACE inhibitor in a fragile/brittle inpatient

The administration of ACE inhibitors to paediatric patients should be done cautiously and with close monitoring in neonates, fragile infants, volume depleted post-surgical patients and those with severe ventricular impairment. May require lower doses and a more gradual increment.

  1. Initiation: Start with test dose of 0.1mg/kg
    - Blood pressure should be checked ½ hourly for 2 hours, then check again at 4 hours after dose (2 hrs after the last BP recording).

  2. If the blood pressure remains stable the second dose of Captopril can be given - 8hrs after the first
    - at a dose of 0.2mg/kg for the second dose. 
    - Repeat blood pressure as above.
  3. If blood pressure remains stable the third dose of Captopril can be given 8hrs after the second
    - at a dose of 0.3mg/kg for the third dose 
    - Repeat blood pressure as above.

  4. Dose increment of Captopril can occur at EACH dose rather than daily or at every second day in the non-neonatal group who are well hydrated and haemodynamically stable.

  5. A maintenance dose of Captopril should be achieved before converting to other longer acting ACE inhibitors which can be given as once or twice daily doses - see Table 2.

  6. Monitoring: Monitoring of serum electrolytes is essential with special care if on concurrent diuretics or potassium sparing agents.

Outpatients: up titration of Captopril in the outpatient setting

There is now over 25 years clinical experience of ACE inhibitor use in children. It is very rare for symptomatic hypotension to occur with dose titration thus blood pressure monitoring is not usually necessary in children over 1 year of age following incremental dose increase in the outpatient setting.

Older children not in heart failure do not need close BP monitoring as they can report any symptoms of dizziness or syncope, which is a better indication of symptomatic hypotension in children. If dizziness occurs the child should be assessed, and usually necessitates returning to the previous dose level for a longer period.

In infants (< 1 year) who are haemodynamically stable; blood pressure monitoring is usually only indicated for the first dose, with monitoring following incremental increase in ACE inhibitors individualised.

  • Monitoring following first dose of ACE: Blood pressure ½ hourly for 2 hours, then discharge if stable.

Routine Screening of renal function:

  • not usually indicated but may be considered on an individual basis for example; a fragile infant

  • ensure potassium sparing agents (Amiloride or Spironolactone) have been stopped

Family education:

  • Ensure family have new script and are aware of new dose and how to draw up and administer increased dose of ACE inhibitor.

  • Educate child and family of signs of symptomatic hypotension (Infants may demonstrate lethargy, lack of interest in feeding. Older children may experience presyncope and syncope).

  • Ensure family have ACE inhibitor patient information pamphlet/paediatric captopril pamphlet.

Table 2: Approximate dose equivalent for frequently used ACE inhibitors in paediatric cardiology
Drug Approximate daily equivalence Maximum Daily Dose (mg/day) in Adults Dosing regimen
Captopril (Capoten®) 12.5 mg TDS  150 (50mg TDS) TDS
Enalapril (Renitec®)
* Half life is 7 hours. NOT to be used as daily regimen (5) 
5mg BD 40mg (in 2 divided doses) BD 
Lisinopril (Prinivil®, Zestril®)  10 mg daily  80  DAILY 
Quinapril (Accupril®)  10 mg daily  40  DAILY 
Cilazapril (Inhibace®)  2.5 mg daily  10 (adult dose usually 5mg daily)  DAILY 

Disclaimer: Note that there are variations in published ACE conversion tables. As such this table does not represent exact or equivalent dosing conversions and should be used as an approximate guide only. Doses are rounded to nearest tablet size. Therefore patients will require appropriate monitoring after changing to a different ACE inhibitor and may require further dose adjustment according to patient tolerance and response.

Nursing Care Plan

ACE inhibitor/Beta blocker medication increase 

Information for Families

ADHB Pharmacy patient information brochure on ACE inhibitors

ADHB Pharmacy patient information leaflet on Captopril for paediatric use

References

  1. Angiotensin Converting Enzyme Inhibitors (ACEIs) Clinical Pearls for the Washington Rx Therapeutic Interchange Program (TIP) Chrystian Pereira, PharmD, Pharmacy Practice Specialty Resident, Family Medicine, Harborview Medical Center
  2. Clinical Services Unit Pharmaceutical Science Vancouver Clinical Services Website. http://www.vhpharmsci.com/
  3. ACE Inhibitors in Pediatric Patients with Heart Failure: K. Momma, Pediatr Drugs 2006;8 (1)55-69
  4. Woods, DJ (editor), New Zealand Formulary for Children [Internet]. 2015 [updated 2015 Sept 1; cited 2015 Sep 4]. Available from: www.nzfchildren.org.nz
  5. Royal Children's Hospital Melbourne. (2002) Editors Kemp, C. and McDowell, J. Paediatric Pharmacopoeia 13th edition. Pharmacy department, Royal Children's Hospital, Melbourne, Australia.
  6. Leversha AM, Wilson NJ, Clarkson PM, Calder AL, Ramage MC, Neutze JM. Efficacy and dosage of enalapril in congenital and acquired heart disease. Archives of Disease in Childhood 1994;70:35-9.
  7. PHARMAC (Pharmaceutical Management Agency) & Health Funding Authority. Changes to the funding of ACE inhibitors and statins: An opportunity to review patient treatment and management. June 1998. Wellington, New Zealand. Available from  www.pharmac.health.nz/news/notification-2014-01-30-captopril

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Document Control

  • Date last published: 13 April 2016
  • Document type: Drug Dosage Guideline
  • Services responsible: Paediatric Cardiology
  • Author(s): Nigel Wilson, Marion Hamer, Elizabeth Oliphant
  • Review frequency: 2 years