Pharmacologic Therapy in Heart Disease

Rafael Mena MDDecember 3rd 2010

Cardiac Medications of Interest in NICU

• Inotropes and vasopressors• Prostaglandins• Antihypertensives• Diuretics context CHF

MAP

• Cardiac Output X SVR

Inotropes and Vasopressors

• Epinephrine• Milrinone• Hydrocortisone

Hypotension

• Difficult to define and measure• MAP and Gestational age• Consensus end organ damage not beneficial• ? Treatment decreases mortality and adverse

long-term outcomes

Current definitions of hypotension do not predict abnormal HUS findings in preemies

• Measured Hypotension 84 infants <30wks via UAC’s in first 72 hours

• 3 definitions of hypotension• HUS lesions were not predicted by any of the

definitions or MAP variability• Blood pressure management alone might not

prevent injury

Limperopouloset al Pediatrics November 2007

Early systemic hypotension and vasopressors in LBW: Impact Neurodevelopment

• Prospective study evaluating effect on neurodevelopment with inotropes in LBWI

• 130 infants. Half treated with Epinephrine and Dopamine. The rest control group

• Outcome measures: Cranial US and neurodevelopment at 2 years

• No differences between groups in neurodevelopment and developmental delay

• Inotropes seem be safe

Pellicer et al, Pediatrics May 2009

Epinephrine and others

Courtesy Beth Ann Johnson

G proteins

Epinephrine vs. Dopamine in LBWI

• Prospective RCT in 60 newborns <1500g. Dopamine dose 2-10ug/kg. Epinephrine 0.1 to 0.5 ug/kg

• Similar effectiveness in raising BP• Epinephrine more hyperglycemia and increase

lactate (Beta stimulation not hypoperfusion)• No difference PDA,BPD,NEC,ROP• Epinephrine could be used first line

Valverde et al, Pediatrics May 2006

Previous studies

• Have reported a decrease in cardiac performance with dopamine

• Higher doses,>10 ug/kg might lead to increase in SVR and leading to myocardial depression

• Different Dopamine studies prefer 2-10 ug/kg dose in preterm infants with impaired CV function

Milrinone

• Inhibitor of phosphodiesterase III (cardiac and vascular tissues)

• In cardiac muscle, CAMP, potentiates Calcium delivery (Inotrope)

• Vascular smooth muscle, CAMP produces relaxation( decrease SVR)

Afterload Reducer

• LV afterload reduction due to decrease in total peripheral resistance and a resulting increase in CO

• Decreases PVR resulting in biventricular afterload reduction

Side effects

• Hypotension• Thrombocytopenia• Arrythmias

Efficacy and safety of milrinone in preventing LCOS in infants and children after corrective surgery for CHD

• PRIMACORP study• Prophylactic Intravenous Use of Milrinone

After Cardiac Operation in Pediatrics• Circulation 2003

PRIMACORP study

• Evaluate the safety and efficacy of prophylactic Milrinone in pediatric patients at high risk of developing LOCS

• Multicenter(31), randomized, double blind, placebo controlled

Results

Hoffman et al, Circulation 2003

PRIMACORP study

• The results show a 64% relative risk reduction in the development of LOCS with the prophylactic use of high dose milrinone

• High dose milrinone: 75 ug/kg bolus, followed by a 0.75 ug/kg/min infusion for 35 hrs

Milrinone improves oxygenation in newborns with severe PPHN

• Many neonates with severe PPHN are poor responders to NO

• 9 full term infants with severe PPHN, OI>20, failure of INO therapy, ECHO confirmation received Milrinone median 70 hrs

• OI marked better especially first 24 hrs• No systemic hypotension

Mcnamara et al, Journal of Critical Care 2006

Hydrocortisone

• Preemies can have a transient adrenal insufficiency

• Improves cardiovascular stability• Dexamethasone impairs neurodevelopment,

does hydrocortisone?

RCT of a stress dose of Hydrocortisone for refractory hypotension in premature infants

• Assess effectiveness of a hydrocortisone stress dose in infants with refractory hypotension

• Prospective RCT of 48 infants with hypotension

• 24 had Dopamine + Hydrocortisone• 24 had Dopamine + placebo• Stress dose hydrocortisone dose 1mg/kg every

8 hrs 5 days

Ng et al, Pediatrics 2006

Hydrocortisone for refractory hypotension works

• Hydrocortisone group weaned vasopressor support faster

• 2 in HC group vs. 11 infants in placebo group required an additional vasopressor

• Preferable than Dexamethasone, but caution

• Prostaglandins

When Prostaglandins are not enough: Lesions likely to require urgent intervention after delivery

• HLH with intact atrial septum• TGA with restrictive ASD• TAPVR with obstruction• TOF with absent pulmonary valve

Hypoplastic Left Heart with intact

atrial septum

1) Hypoplastic ascending aorta and aortic arch

2) Hypoplastic Left Ventricle3) Large PDA supplying the

only source of blood flow to the body

4) ASD allowing blood return from the lungs to reach single ventricle

Transposition Great Arteries with restrictive ASD

1) Aorta arising from the RV(poor Oxygenated blood body)

2) Pulmonary artery arising from LV(well oxygenated blood back to lungs)

Total Anomalous Pulmonary Venous Return with Obstruction

Supracardiac Infracardiac

Blood return to SVC Blood Return to Hepatic Veins, then IVC. Most common type to be Obstructed

Tetralogy of Fallot with absent Pulmonary Valve1) Severely dilated main and branch pulmonary arteries causing external bronchial compression

Examples of ductal dependent lesions

• Left sided lesions-Coarctation of Aorta-Critical Aortic Stenosis• Right sided lesions- Tricuspid/Pulmonary Atresia• TGA

Neoreview Question• You are reviewing the records of a 5-month-old African American female

infant in the neonatal intensive care unit. She was delivered at 36 weeks' gestation with an antenatal diagnosis of truncus arteriosus and interrupted aortic arch. Postnatal echocardiography confirmed the antenatal findings and revealed ductus-dependent coronary circulation. The infant has been receiving alprostadil infusion since birth and is awaiting heart transplantation. She was also diagnosed to have Di George syndrome with hypoparathyroidism and immunodeficiency, and is receiving calcitriol, calcium glubionate, and bactrim prophylaxis. She is receiving decongestive therapy with furosemide and aldactone. She is also receiving metoclopramide for gastroesophageal reflux. The resident physician reports firm swelling of both forearms without any tenderness, erythema, fluctuation, or signs of inflammation. Complete blood count measurement taken the same day shows normal findings for age. You request radiography of the forearms.

Describe Figure

Hyperostosis

• Long treatment(>40 days)• Clavicle is most frequent site• No long term problems with bone growth

once stopped

Other complications

• Fever• Hypotension• Apnea

• Drugs for neonatal hypertension

Sounds familiar?

• An ex 24 wk now 37 wks old is on full feeds and ready to go home. You are rounding and the nurse brings to your attention that his systolic pressures have been >110 for the past 3 days. Work up including renal labs and US, urine Ca to creatinine ratio is normal. What are your therapeutic choices?

Systemic hypertension in VLBW infants with BPD

• Purpose: determine if systemic HTN occurred in VLBW with BPD

• 73 patients in their cohort , which 41 had BPD and 12% of them had HTN

• The hypertensive infants all had BPD and longer hospital stay

• Infants with severe BPD risk of hypertension

Alagappan et al, Am J Perinatol 1998

Age specific percentiles of blood pressure measurement (n=13,000 infants)

Age in months Systolic BP’s 95% Systolic BP’s 50%

1 108 85

2 108 85

3 110 90

4 110 90

Report of the Second Task Force of Blood Pressure Control in Children

Important tests in Neonatal Hypertension

• Renal panel• Calcium• Renal US with Doppler

Useful Oral Agents

Drug Class Dose Comments

Captopril ACE inhbitor From 0.01mg/kg up to 6mg/kg

CommonMonitor K and creatinine

Amlodipine Channel blocker From 0.1 to 0.6 mg/kg

Being used more often

Hydrochlorothiazide Thiazide 20-40mg/kg/day Monitor electrolytes

Flynn, Pediatric Nephrology 2000

Mechanism of Action

Drug Mechanism of Action

Ace Inhibitors Blocks angiotensin converting enzyme, thus decrease in Angiotensin 2 leading to vasodilation and less salt retention

Calcium Channel Blockers Relaxation of vascular smooth muscle

Thiazide diuretics Inhibits Na in the distal tubule, natriuresis

• Diuretics in context of Heart Failure

Recent UC case

3 wk old former 37 weeker with Trisomy 21 with known AV canal. Initially taking almost 80% PO. As weeks progressed, she got more tachypneic, was barely taking PO and had hepatomegaly on physical exam. Started on Lasix, Aldactone and afterwards in Captopril.

Diuretics

• Lasix works in loop of Henle and is has strong Natriuresis

• Aldactone weak diuretic and potassium sparing

• Alleviate pulmonary edema and overcirculation seen in heart failure

Spironolactone therapy in infants with CHF secondary to CHD

• Studied the efficacy of spironolactone on heart failure in 21 patients under 1 year

• All received Digoxin and Chlorothiazide• 10 without vs. 11 with Aldactone• Improved hepatomegaly and reduction in

weight• Addition of Aldactone can improve symptoms

in heart failure patientsHobbins, Archive of Disease in Childhood 1981

?????????????????

• Thanks

References1) Pellicer et al,Early systemic hypotension and vasopressor support in LBWI:

Impact on Neurodevelopment, Pediatrics 2009 123:13692) Limperoupoulos et al, Current definitions of hypotension do not predict

abnormal cranial US finding in preterm infants, Pediatrics Nov 2007;120, 966-977

3) Valverde et al, Dopamine vs. Epinephrine for cardiovascular support in LBWI: Analysis of systemics effect and neonatal clinical outcomes, Pediatrics 2007;117, 1213-1222

4) Hoffman et al, Efficacy and Safety of Milrinone in preventing low cardiac output syndrome in infants and children after corrective surgery for congenital heart disease, Circulation 2003;107:996-1002

5) Mcnamara et al, Milrinone improves oxygenation in neonates with severe persistent pulmonary hypertension of the newborn, Journal of Critical Care 2006;21:217-223

5) Ng et al, A double blind Randomized controlled study of a dose of Hydrocortisone for Rescue treatment of refractory hypotension in preterm infants, Pediatrics:110, February 2006

6) Alagappan et al, Systemic hypertension in VLBW with BPD: incidence and risk factors. Am J Perinatol Jan 1998;15(1) 3-8

7) Flynn, Neonatal Hypertension : Diagnosis and Management, Pediatric Nephrology 2000 14:332-341

8) Hobbins et al, Spironolactone therapy in infants with congestive heart failure secondary to congenital heart disease, Archives of Disease in Childhood, 1981, 56:934-938