Donna M. Kraus, Pharm.D.
Spring 1998

Clinical Pharmacotherapeutics II
Pediatrics
Cardiovascular Therapy

  1. Introduction
  2. Congenital Heart Diseases (CHD)
  3. Hypertension5

 

Goals:

1. To familiarize the student with the more common congenital heart abnormalities and their treatments.

2. To expand the students' knowledge base with regard to the pathophysiology and pharmacotherapy of pediatric hypertension.

Objectives:

1. Describe in detail the normal fetal circulation and the cardiovascular adjustments which occur after birth.

2. Delineate the pathophysiology and clinical manifestations of patent ductus arteriosus.

3. Describe a therapeutic plan to treat an infant with a significant patent ductus arteriosus, including appropriate dosing recommendations and monitoring parameters.

4. State the indications, adverse effects, monitoring parameters and dose of prostaglandin E1 (Alprostadil) as used in the management of congenital heart diseases in infancy.

5. Define normal, high normal, and high BP (hypertension) as the term applies to the pediatric population.

6. Describe the commonest causes by age group of chronic sustained hypertension in children.

7. List the indications for nonpharmacologic interventions and indications for antihypertensive drugs.

8. State the therapeutic goals of antihypertensive drug therapy of childhood hypertension.

9. Describe the stepped-care approach to antihypertensive drug therapy.

10. Given a case history, outline a pharmacotherapeutic plan for the treatment of a hypertensive child, include rationale of choice of agent, and monitoring parameters.

 

Highly Suggested Reading:

1. Kraus DM, Hatzopoulos FK. Chapter 96: Neonatal Therapy in Applied Therapeutics: the Clinical Use of Drugs 6th ed. Young LY, Koda-Kimble MA eds. Applied Therapeutics, Inc, Vancouver, WA, 1995; pages 96-11 through 96-14.

Suggested Readings:

1. Dooley KJ. Management of the Premature Infant with a Patent Ductus Arteriosus. Pediatrics Clinics of North America, Vol 31, No. 6, December 1984, 1159-1172.

2. Heymann MA, Clymann RI. Evaluation of Alprostadil (Prostaglandin E1) in the Management of Congenital Diseases in Infancy. Pharmacotherapy 1982; 2:148-155.

3. Report of the Second Task Force on Blood Pressure Control in Children - 1987. Pediatrics 1987; 79: 1-25.

 


PEDIATRIC CARDIOVASCULAR THERAPY

I. Introduction

In adult animals blood returns from the systemic circulation to the right side of the heart, goes to the lungs where it is oxygenated, then goes to the left side of the heart and back to the systemic circulation. This "pathway" is very different in the fetus.

A. Normal Fetal Circulation: (see figure 13-27)1 Three main structural differences exist in the fetal circulation.

1. Ductus Venosus: Structure which allows umbilical venous blood to bypass the liver.

2. Foramen Ovale: Opening which allows blood from the right atrium to pass to the left atrium.

3. Ductus Arteriosus: Structure which connects the pulmonary trunk (artery) to the descending aorta and allows blood to bypass the lungs.

 

Blood which has been oxygenated in the placenta, returns to the fetal body through the umbilical veins. Approximately 50 % of umbilical venous blood will bypass the hepatic microcirculation by going through the ductus venosus and directly into the inferior venous cava. (The other 50 % of umbilical venous blood will pass into the portal veins through the hepatic circulation and into the inferior vena cava via the hepatic veins.) Blood from the inferior and superior venous cava enter into the right atrium.

The higher oxygenated blood, which came from the umbilical vein through the ductus venosus into the inferior vena cava, enters the right atrium and streams preferentially across the foramen ovale to the left atrium. This relatively higher oxygenated blood then enters the left ventricle, goes into the aorta and perfuses the head and upper trunk.

The blood that comes from the superior vena cava (and the distal inferior vena cava) also enters the right atrium, but this blood goes through the tricuspid value into the right ventricle (a small amount may cross the foramen ovale). From the right ventricle, blood is ejected into the pulmonary artery and passes through the ductus arteriosus into the descending aorta. Only a small amount of blood travels from the pulmonary artery into the pulmonary circulation. Blood which returns from the pulmonary circulation enters the left atrium.

1. Fetal oxygen tension: The oxygen tension of fetal arterial blood is considerably lower than that of an adult. As already mentioned above, blood with a higher oxygen tension is delivered to the head and upper and upper trunk of the fetus.

Umbilical venous blood 30-35 torr
Inferior vena cava (entering heart) 26-28 torr
Superior vena cava 12-14 torr
Right ventricle & pulmonary artery 18-19 torr
Left ventricle & ascending Aorta 23-25 torr
Descending aortic blood 20-22 torr

 

2. Fetal myocardial performance

a. There is a limited ability of the fetal heart to increase its stroke volume. This is due to several factors including: fewer contractile elements in the fetal vs adult cardiac muscle, possible differences in metabolism of fetal vs adult muscle and the lack of complete sympathetic innervation of the fetal heart.

b. Fetal cardiac output is more sensitive to heart rate

HR 160 --> 240 = 10-15% increase in cardiac output

HR 160 --> 120 = 20-25% decrease in cardiac output

 

B. Cardiovascular Changes After Birth

1. Cessation of umbilical-placental circulation leads to:

a. Reduction of venous return through inferior vena cava

b. Reduction of blood flow through ductus venosus

c. Closure of ductus venosus within 3-7 days after birth

2. Changes in pulmonary circulation: The fetus has very low pulmonary blood flow due to the high pulmonary vascular resistance. A moderate decrease in pulmonary vascular resistance is seen during the several weeks before birth due to an increase in the number of pulmonary blood vessels. A dramatic decrease in pulmonary vascular resistance is seen at birth due to the vasodilator effect of ventilation of the lungs with oxygen. This decrease in pulmonary vascular resistance results in a significant increase in pulmonary blood flow and a decrease in pulmonary arterial pressure. (see figure 26-42)

3. Closure of foramen ovale

a. Occurs due to the decrease in right atrial pressure and small increase in left atrial pressure.

b. The foramen ovale is functionally closed by the third month of life

c. The foramen ovale may re-open and result in a right to left shunt

4. Closure of ductus arteriosus

a. The ductus arteriosus constricts rapidly after birth

b. Functional closure occurs within 10-15 hours after birth

c. Permanent closure is usually complete within 3 weeks

d. Mechanism of closure: vasoconstriction and closure of the ductus arteriosus are thought to be due to:

1. Increases in p02

2. Decreases in circulating PGE2 (due to the removal of the placenta)

5. Cardiac output: Increases immediately after birth

  Right Ventricle Left Ventricle
fetus 330 ml/kg/min 170 ml/kg/min
birth 400 ml/kg/min 400 ml/kg/min
8-10 weeks   150 ml/kg/min
adult level   70-80 ml/kg/min

NOTE: The newborn has a limited ability to raise cardiac output further as compared with adults (i.e., the newborn has an overall decrease in cardiac reserves. The cardiac reserve is the difference between resting performance and performance at peak capacity. In other words, the newborn's cardiac function is close to its peak performance.)

6. Heart rate: Increased at birth (vs adult) and gradually decreases with age. (Review notes from first Peds lecture)

Resting fetal heart rate 160 - 180 beats per minute
Newborn (awake) 140 - 160 (120 asleep)

 

7. Blood pressure: Systemic blood pressures are lower in newborns vs adults and increase with age. BP of a fetus at term = 60/30, while a BP for a term infant = 70/50.


II. Congenital Heart Diseases (CHD)

A. Incidence

1. Overall incidence: Congenital heart diseases occur in about 8 to 10 of 1000 live-born infants. Two to three per 1000 infants with CHD will be symptomatic in the 1st year of life.

2. Incidences of specific lesions: (table 26-6)2

B. Etiology: CHD is most likely due to an interaction between a genetic predisposition and environmental factors.

1. Genetic factors: Certain chromosomal abnormalities may cause CHD as part of a complex syndrome. For example 50% of Down's syndrome patients may have a CHD.

2. Environmental factors such as viruses (e.g., rubella) or fetal exposure to certain drugs or substances via maternal exposure may also cause CHD. Examples: Lithium, ethanol, retinoic acid, progesterone. Also, diabetic mothers may have an increase risk of CHD in their children.

C. Left to Right Shunts (acyanotic) (See Table 26-72)

1. General features

a. A left to right shunt is a shunting of blood from the systemic circulation to the pulmonary circulation through an abnormal communication.

b. A left to right shunt allows oxygenated blood to recirculate through the lungs without entering the peripheral arterial circulation.

 

2. A ventricular septal defect (VSD) is the most common CHD. Atrial septal defects (ASD) are also common. With a VSD there is a defect (a hole or opening) in the ventricular septum (myocardial tissue that separates the ventricles). Likewise with an ASD, the defect or hole is between the atrium. These defects allow blood to flow from the left side of the heart to the right side of the heart i.e., left to right shunt.

 

2. Patent ductus arteriosus (PDA): As you recall, in the fetus, the ductus arteriosus normally diverts blood from the pulmonary artery to the descending aorta, thus bypassing the pulmonary vasculature bed. Normally, the ductus arteriosus closes after birth. If, however, the ductus arteriosus stays open (patent) after birth, then a left to right shunt can occur through the ductus. NOTE: This flow through the ductus is in the opposite direction as it is in the fetus due to a higher pressure in the aorta after birth.

a. The incidence of PDA is dependent upon infant maturity and weight at birth.

1. full term infants: 1 in 2500-5000 live births

2. premature infants (all birth weights): 20.2% incidence with significant PDA occurring in 12%.

3. 30 - 40% of premature infants with birth weight < 1750 grams

4. 80% of premature infants with birth weight < 1000 grams

b. Pathophysiology of PDA

With a PDA there is a left to right shunt through the PDA (i.e., blood flows from the aorta through the PDA and into the pulmonary arteries). This increases the blood in the pulmonary circuit and increases the blood returning to the left side of the heart. This increases the workload on the left side of the heart and leads to:

c. Identification and diagnosis of PDA: The clinical features of a PDA depend upon the magnitude of the left to right shunt and the maturity of the infant. Premature infants may present earlier and may have more symptoms with smaller shunts compared to term infants.

1. Cardiac murmur: Infants with a PDA may have a systolic murmur which is best heard at the middle to upper left sternal border. It usually occurs on the 3rd to 4th day of life. Up to 11 % of infants with a PDA will NOT have a murmur. The murmur may sound rough and irregular "rocky" in premature infants and in older infants may be a "continuous machinery" type.

2. Clinical features of a PDA:

A. 47 % of infants have a hyperactive precordium.

B. 50 % have bounding pulses with a wide pulse pressure (>35).

C. 11 % are tachycardia (HR > 170). A gallop rhythm is common.

D. 15 % have tachypnea (respiratory rate > 70 breaths per minute).

E. 5 % have hepatomegaly (liver edge > 3 cm below the right costal margin.

3. Chest x-ray: A cardiac to thoracic ratio > 65 % indicates cardiomegaly.

4. Echocardiogram: The ratio of the left atrial diameter to aortic root diameter is increased (> 1.4:1) indicating an increase in left atrial volume secondary to the left to right shunt.

d. Management

1. Fluid restriction: NOTE: Fluid overload can cause a PDA by opening the ductus arteriosus.

A. Rationale for fluid restriction: By decreasing volume, the workload of the heart will be decreased.

B. Decrease fluids to 80 - 100 ml/kg/day. (Add 20 ml/kg/day if radiant warmer is used)

2. Diuretics:

A. By causing a diuresis, a decrease in intravascular volume will result, which will also decrease the workload of the heart. A decrease in left ventricular end diastolic volume (preload) and pulmonary venous pressure will also be seen. The effects of pulmonary edema will be decreased and an increase in lung compliance will be seen. Blood gases may improve.

B. Furosemide 1-2 mg/kg/dose

3. Transfusion:

A. Rationale: Avoid anemia and a resultant increase in workload on the heart.

B. Desired hematocrit = 45

4. Indomethacin

A. Rationale: Since a decrease in prostaglandins is thought to naturally close the PDA, prostaglandin inhibitors should decrease the concentration of prostaglandins and therefore close a PDA.

B. A collaborative placebo controlled study3 (n=421) demonstrated the efficacy of indomethacin for PDA closure. Only 35% of infants receiving placebo (usual medical treatment alone) had PDA closure as compared to 79% of patients receiving indomethacin and usual medical treatment.

C. Contraindications: infants with necrotizing enterocolitis, impaired renal function (do not use if BUN > 25 or SCr > 1.0mg/dl), intraventricular hemorrhage, active bleeding or thrombocytopenia (caution with platelets < 80,000).

D. Adverse effects:

Renal: Dilutional hyponatremia, oliguria, hyperkalemia

Gastrointestinal: nausea, vomiting, epigastric / abdominal pain, GI hemorrhage

Hematologic: inhibition of platelet aggregation, thrombocytopenia

Other: Hypoglycemia, displacement of bilirubin from albumin binding sites

E. Monitoring parameters: Ins and Outs, urine output cc/kg/hour, serum electrolytes, CBC with platelets, NG aspirate and stools for blood (also guaiac or hemocult), abdominal girth (for NEC).

F. Doses are given IV every 12 -24 hours x 3

Initial: 0.2 mg/kg. Subsequent doses dependent upon age at onset of treatment.

< 48 hours: 0.1 mg/kg q 12 hours X 2

2 - 7 days old: 0.2 mg/kg q 12 hours X 2

> 8 days old: 0.25 mg/kg q 12 x 2

G. IV Administration: Doses should be infused IV over 30 minutes. DO NOT GIVE IV PUSH as significant decreases in GI blood flow may occur. (Decreases in GI blood flow may be associated with GI bleeding, perforation, or NEC.)

 

NOTE: Indomethacin is less effective if started after 7 - 10 days of life. Also, current studies are investigating lower doses of indomethacin used for up to 7 days in order to decrease reopening of the PDA and retreatment.

5. Surgical intervention: Ligation of the ductus arteriosus may be needed. Some centers prefer surgical ligation to medical closure with indomethacin.

D. Regurgitant lesions are those in which blood ejected by either the right or left atrium or ventricle returns to that chamber through an incompetent AV or semilunar valve. (These will not be discussed)

1. Mitral valve regurgitation

2. Aortic root regurgitation

3. Tricuspid valve regurgitation

4. Pulmonic valve regurgitation

E. Obstructive Lesions (table 26-9 and 26-102)

NOTE: Mild or moderate obstruction is called stenosis, whereas complete obstruction is termed atresia. With atresia blood is diverted from its normal pattern of flow and is directed through abnormal pathways in order to maintain systemic or pulmonary blood flow. (You will only be responsible for ductal dependent obstructive lesions, see prostaglandin E1 below)

 

F. Right to Left Shunts (cyanotic)

1. General features

a. Systemic venous (unoxygenated) blood passes into the systemic arterial circulation i.e., this is a venous-to-arterial shunt.

b. These right to left shunts result in cyanosis, clubbing, and polycythemia.

c. Causes of cyanosis in newborns (see table 26-112)

d. Cyanotic malformations associated with altered pulmonary blood flow (see table 26-122)

 

G. Prostaglandin E1 (Alprostadil) 4

1. Indications

a. Prostaglandin E1 is indicated for palliative therapy to temporarily maintain the patency of the ductus arteriosus (i.e. to keep the ductus arteriosus open) until corrective or palliative surgery can be performed.

b. Prostaglandin E1 is indicated for the following ductus -dependent congenital heart diseases. These CHDs need the ductus arteriosus to remain open (patent) in order for proper circulation to take place.

1. Cyanotic ductus arteriosus dependent CHD

  • Pulmonary atresia
  • Pulmonary stenosis
  • Tetralogy of fallot
  • Tricuspid atresia
  • Transposition of the great vessels

2. Acyanotic ductus arteriosus dependent CHD

  • Coarctation of aorta
  • Interrupted aortic arch
  • Hypoplastic left heart

 

2. Pharmacology

a. Causes relaxation of the smooth muscle of the ductus arteriosus resulting in vasodilation (opens the ductus)

b. Inhibits platelet aggregation

c. Causes stimulation of intestinal and uterine smooth muscle

d. Inhibits gastric secretions

3. Pharmacokinetics

a. Prostaglandin E1 is rapidly metabolized by oxidation in the lungs, up to 68 - 80 % in a single pass.

b. The t1/2 = 5 to 10 minutes (Must be given as continuous infusion)

c. Excreted by the kidneys

d. Weekly bound to albumin

4. Adverse Effects

a. CNS

Apnea occurs in 10 - 12 % of infants receiving prostaglandin E1. Apnea occurs most often within the first hour of infusion in infants who are < 2 kg.

Fever: seen in 14 % of patients

Seizures: 4 %

b. Cardiovascular

Flushing: 10 % incidence (more common with intra-arterial infusions)

Bradycardia: 7 %

Hypotension: 4 %

Tachycardia: 3 %

c. Respiratory

Bradypnea

Respiratory depression

d. Gastrointestinal

Diarrhea: 2 %

Gastric regurgitation

e. Hematologic: Bleeding disorders

f. Skeletal

Cortical proliferation of the long bones has been seen with long term infusions. Cortical proliferation regresses after withdrawal of the drug.

5. Monitoring parameters: Blood gases, O2 saturation, blood pressure, respiratory rate, temperature, heart rate.

(NOTE: Decrease the rate of infusion if pyrexia or hypotension occurs; if apnea or bradycardia occurs, the drug should be discontinued and cautiously institute at a lower dose once adverse effects subside)

6. Prostaglandin E1 Dosage and administration

a. Initial Dose: 0.1 micrograms per kg per minute

b. Reduce the dose after a therapeutic response is achieved.

1. For infants with restricted pulmonary blood flow, (i.e., those who have cyanotic ductus dependent CHD with hypoxia) an increase in p02 is desired.

2. For infants with restricted systemic blood flow, (i.e., acyanotic ductus dependent CHD with hypoperfusion to lower organs and extremities) an increase in systemic blood pressure and blood pH is desired.

c. As desired therapeutic response is seen, reduce the dose from 0.1 to 0.05 micrograms/kg/minute. Then reduce the dose to 0.025 and to 0.01 microgram/kg/minute, if possible.

d. If the initial dose does not produce an adequate response, increase the dose. The maximum recommend dose is 0.4 micrograms/kg/minute.

e. Prostaglandin E1 can be given IV or IA (intra-arterially), however the IV route of administration is preferred.

f. Usually 500 mcg is diluted in 25 - 250 ml of 0.9% NaCl or D5W.

7. IV compatibilities: Unknown: Do not mix with other drugs.


III. Hypertension 5

 

A. Bp Measurement in Children

1. Problems

a. Hypertension may be wrongly diagnosed because of the use of too small of a blood pressure cuff. In pediatric patients there may be more of a chance for measurement errors since there is a greater range in arm sizes.

b. It may be difficult to obtain an accurate blood pressure reading in a child who is anxious or restless.

c. Since vein size also varies in the pediatric population, errors may occur with improper pressure on the stethoscope.

d. Interpretation of blood pressure readings is more complex as the "normal" blood pressure increases with age. Likewise, the blood pressure reading which would indicate hypertension increases with age.

2. Instruments: In infants, blood pressure may be difficult to obtain by auscultation and manometer use. Ultrasound devices, such as the Doppler, or the Dynamap oscillometric unit may need to be used.

3. Cuff size (table 2)

 

 

H. Treatment

1. Nonpharmacologic

a. weight reduction

b. physical conditioning

c. dietary modification

2. Pharmacologic therapy

REFERENCES

 

1. The Cardiovascular System in Textbook of Pediatrics, 12th edition. Nelson WE, editor. 1983 WB Saunders Company, Philadelphia PA.

2. The Circulatory System in Rudolph's Pediatrics, 19th edition, Rudolph AM, editor. Appleton & Lange, Norwalk, Connecticut, 1991.

3. Gersony WM, Peckham GJ, Ellison RC et al. Effects of indomethacin in preterm infants with patent ductus arteriosus: Results of a national collaborative study. J. Ped, Vol 102, No 6, June 1983; 895-906.

4. Roehl SL, Townsend RJ. Alprostadil. DICP, VOl 16, Nov 1982; 823-832.

5. Report of the Second Task Force on Blood Pressure Control in Children - 1987. Pediatrics, Vol 79, No 1, January 1987; 1-25.

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