Cardiology: NICU Handbook

Antiarrhythmic drugs¹

Jeffrey L. Segar, MD
Peer Review Status: Internally Peer Reviewed

¹Portions of this information were derived from adult patients

References: Gelband and Rosen, 1975; Guntheroth, 1978; Somogyi et al, 1981; Schreeweiss, 1990; Roberts, 1984

Edward F. Bell, MD
Peer Review Status: Internally Peer Reviewed 9/13/12

The following figures can be used to assess normal blood pressure in young premature infants. As a rough rule of thumb, the lower limit of normal mean blood pressure in mm Hg on the day of birth is approximately equal to the gestational age in weeks (Lee J et al, 1999). Hypotension should not usually be treated without other signs of insufficient cardiac output (e.g. poor skin perfusion, metabolic acidosis, anuria and so forth).

The figures below are the mean and 95% confidence limits for blood pressure during the first 12 hours after birth, (Versmold HT et al, 1981). 

Open diagram

Systolic, diastolic, and mean blood pressure

Systolic (a), diastolic (b), and mean (c) blood pressure of preterm infants on Day 1 of life by birth weight (a1, b1, c1) and gestational age (a2, b2, c2). The lines represent mean ± 2 SD (Pejovic B et al, 2007). 

Pulse

Mean blood pressure during the first week of life for very-low-birth-weight infants subdivided into four birth weight groups (Cunningham S et al, 1999). 

References:

Cunningham S, Symon AG, Elton RA, Zhu C, McIntosh N. Intra-arterial blood pressure reference ranges, death and morbidity in very low birthweight infants during the first seven days of life. Early Hum Dev 1999;56:151-165.

Lee J, Rajadurai VS, Tan KW. Blood pressure standards for very low birthweight infants during the first day of life. Arch Dis Child Fetal Neonatal Ed 1999;81:F168-F170.

Pejovic B, Peco-Antic A, Marinkovic-Eric J. Blood pressure in non-critically ill preterm and full-term neonates. Pediatr Nephrol 2007;22:249-257.

Versmold HT, Kitterman JA, Phibbs RH, Gregory GA, Tooley WH. Aortic blood pressure during the first 12 hours of life in infants with birth weight 610 to 4,220 grams. Pediatrics 1981;67:607-613. 

Jeffrey L. Segar, MD
Peer Review Status: Internally Peer Reviewed

1. "Digitalization" is generally used when treating dysrhythmia. The total loading (digitalizing) dose is administered in three divided doses given every 8 hours. Administer IV slow push over 5 to 10 minutes. Do not administer IM (causes pain and tissue damage). The first maintenance dose should not be given any earlier than 24 hours after the last loading dose in the premature infant and 12 hours in the full-term neonate and infant (1-12 months old).
2. Daily maintenance dose is generally 25% of the digitalizing dose divided into 2 doses. Conversion to oral dosing traditionally involves increasing the intravenous dose by 25 to 30 % because of the assumed bioavailability differences. Whether this dose modification for intravenous to oral administration translates to meaningful pharmacological equivalency in patients is unknown.
3. Dosing the premature infant at 24 hour intervals is based on the prolonged plasma clearance of digoxin. It can be anticipated that renal function will increase sufficiently to require the same recommended dose every 12 hours at approximately one month of age. Measurement of the serum digoxin level will confirm the need for such dosing changes (although in newborns may overestimate injected digoxin levels, because of endogenous digoxin-like substances).
4. Dose should be increased at one month of age to that of the full-term newborn (6 -8 mcg/kg/day). Measurement of the serum digoxin level will confirm the need for such dosing changes.
5. Dose should be increased at one month of age to that of infant (8-12 mcg/kg/day). Measurement of serum digoxin levels will confirm the need for such dosing changes.

References

Preterm - Berman et al (1978), Pinsky et al (1979), Warburton et al (1980), Nyberg and Wettrell (1980), Collins-Nakai (1982b)

Full-Term - Wettrell and Anderson (1977), Nyberg and Wettrell (1980)

Infants - Nyberg and Wettrell (1980)

Download Systemic Hypotension in Premature Infants Guidelines table

Download the Inotropes-and-Vasopressor table.

Jeffrey L. Segar, MD
Peer Review Status: Internally Peer Reviewed

Commonly used vasoactive drugs in the NICU include dopamine, dobutamine, epinephrine, and vasopressin. Since these agents mediate their effects via adrenergic and dopaminergic receptors, an understanding of these receptors is essential for the proper use of vasoactive agents. The following is a brief synopsis of the various receptors, and the physiologic responses resulting from their activation.

(*DA = Dopamine receptor)

Epinephrine

Indications

Cardiac arrest, profound shock, low cardiac output, failing myocardium unresponsive to other inotropic agents.

Dose range

Initial dose 0.05 µg/kg/min. Titrate dose to desired response, not to exceed 1.0 µg/kg/min. An epinephrine dose of 0.05 µg/kg/min. may be more effective than a dose of dopamine at > 15 µg/kg/min.

Mechanism of action

Epinephrine is an endogenous compound formed from norepinephrine. It is principally produced with stress and produces widespread metabolic and hemodynamic effects via effects on b1 , b2 , and a-adrenergic receptors. The effects of epinephrine depend on the dosage selected and the range of plasma concentration achieved in the individual patient. b1 receptors are most sensitive to epinephrine, and are affected by very low plasma concentrations resulting in inotropic and chronotropic effects (that increase myocardial oxygen consumption). Stimulation of b2 receptors leads to vasodilation of splanchnic and skeletal muscle beds. Vasoconstriction from a- receptor stimulation in skin and renal vascular beds occurs at all concentrations, while at higher concentrations, vasoconstriction effects in the pulmonary, splanchnic, skeletal muscle, cerebral, and coronary vascular beds predominate. As the concentration of epinephrine increases, myocardial irritability occurs, manifested by atrial and ventricular dysrhythmias. Metabolic effects occur at higher plasma concentrations, including hyperglycemia from a-adrenergic-mediated suppression of insulin release that leads to ketogenesis, gluconeogenesis, and accelerated glycogenolysis with resulting lactic acidemia. Hypokalemia is attributable to b2 - adrenergic receptors linked to Na+-K+ ATPase in skeletal muscle. Other effects include hypophosphatemia, and activation of lipase.

Adverse effects

Adverse effects include increased myocardial and global oxygen consumption, tachycardia, and hypertension. The extent to which the increased oxygen utilization is balanced by improved coronary blood flow depends on the state of the myocardium. Epinephrine increases pulmonary vascular resistance. In addition, pulmonary arterial and venous pressures increase because of increased systemic to pulmonary shunt, which can lead to pulmonary edema. Higher doses induce widespread vasoconstriction that may terminate in hypertensive crisis, renal failure, and gangrene of distal extremities. Infiltration into local tissues or intra-arterial injection can produce severe vasospasm and tissue injury. If extravasation is followed by pallor and other signs of impaired local perfusion, the attending physician should be notified immediately, and consideration given to local injection of phentolamine (an a-adrenergic antagonist, 0.3 - 0.5 mg of 1 mg/ml solution).

Dopamine

Indication for use

To improve cardiac output, blood pressure, and urine output in critically ill patients with shock, renal failure, and CHF.

Mechanism of action and dose range

To calculate a drip that infuses 10 µg/kg/min. at 1 ml/hr:

multiply weight (kg) by 30 = number of mg Dopamine to add to 50 ml IVF (D5W, D10W, NS, D5NS)

Dopamine is found in sympathetic nerve terminals, the adrenal medulla, and is a central neurotransmitter. Dopamine stimulates D1 and D2 receptors in the brain and in vascular beds of the kidney, mesentery, and coronary arteries. Higher concentrations stimulate b1 and a receptors, and may cause renal vasoconstriction. Dopamine exerts a positive inotropic effect on the myocardium, acting as a b1 agonist. Tachycardia is less prominent during infusions of dopamine than of isoproternol. Dopamine improves myocardial efficiency because coronary arterial blood flow increase more than does myocardial oxygen consumption.

Adverse effects

Through central D2 receptors, dopamine suppresses secretion of thyrotropin and prolactin. It also inhibits release of aldosterone, which may facilitate a desirable diuresis. Dopamine may depress the ventilatory response to hypoxia and hypercarbia. Its effects on insulin secretion and glucose metabolism are similar to epinephrine. A decrease in serum potassium is also frequently noted. Since dopamine promotes release of norepinephrine from synaptic terminal and is also converted to norepinephrine in vivo, even at doses as low as 1.5 µg/kg/min., severe limb ischemia has been reported; risk is particularly increased with extravasation or presence of an arterial catheter. If this occurs, notify attending physician immediately, discontinue dopamine infusion, and in severe cases consider local infiltration with phentolamine administered with a fine hypodermic needle).

Dobutamine

Indications

Inotropic support in patients with shock, hypotension, pulmonary hypertension with hypoxemia

Dose range

2 to 20 µg/kg/min.; usually don’t need doses higher than 15 µg/kg/min.
Usual starting dose range: 2 - 5 µg/kg/min.

Adjust upward in increments of 2 - 3 µg/kg/min., based on desired increase in cardiac output / blood pressure. Doses should be individualized to the patient response is observed within 1 - 2 min., with maximal effect within 10 min. Must be administered by continuous IV infusion because brief half-life.

To calculate a drip, see Dopamine section.

Mechanism of action

Dobutamine is a synthetic catecholamine that primarily produces a significant inotropic effect via b1 -receptor stimulation in the heart) and mild to moderate chronotropic effect. Systemic vascular resistance generally decreases since in the peripheral circulation the b2 effect predominates over the a effect. May see cutaneous vasodilation. It dose not activate dopaminergic receptors, and causes no renal and mesenteric vasodilation. Dobutamine improves renal blood flow by increasing cardiac output.

Adverse effects

May cause hypotension if patient is hypovolemic. Volume loading to ensure adequate preload is recommended before starting dobutamine therapy. Dobutamine usually increases myocardial oxygen demand, but coronary blood flow and oxygen supply increase to keep pace with demand. However, when dobutamine increases heart rate and decreases diastolic time for coronary artery perfusion, myocardial oxygen balance is unfavorably affected. At infusion rates between 7.5 and 10 µg/kg/min, a 10 - 20 % increase in heart rate is generally observed. In the non-asphyxiated neonate, this is generally well tolerated. Dysrhythmia can be induced or exacerbated with electrolyte imbalance, high infusion rates, or myocarditis, although the incidence of dysrhythmia is lower than that reported for dopamine or isoproterenol. Tissue ischemia may occur with infiltration.

Vasopressin Guidelines

Download PDA Screening and Management Guidelines

Edward F. Bell, MD and Jeffrey L. Segar, MD
Peer Review Status: Internally Peer Reviewed

Indomethacin (an inhibitor of prostaglandin synthesis) is sometimes used to promote the closure of a clinically significant PDA. The decision to use indomethacin MUST be discussed with the attending neonatologist.

Serum creatinine, BUN, and platelet count, should be obtained prior to giving indomethacin. A reduced fluid intake prior to indomethacin may improve the congestive heart failure secondary to the PDA, as well as improve chances of PDA closure. Infants should be made NPO prior to indomethacin administration because of the effect of the drug on mesenteric blood flow.

Contraindications:

• Renal Failure
• GI bleeding
• Thrombocytopenia
• Acute NEC

Dose:
1st dose: 0.2 - 0.3 mg/kg IV
2nd dose: 0.2 mg/kg IV 12-24 hours after 1st dose if PDA persists.
3rd dose: 0.2 mg/kg IV 12-24 hours after 2nd dose if PDA persists.

Indomethacin is given IV over 30 minutes, as slower injection may avoid decreased cerebral blood flow after indomethacin.

Indomethacin also has a number of significant non-cardiac effects that should be kept in mind when using this drug. These include a decrease in the blood flow velocities (up to 120 minutes after administration) of the cerebral, renal, and mesenteric vascular beds, an attenuation of ET-suctioning induced increase in cerebral blood flow velocity, an inhibition of platelet aggegation and prolonged bleeding time up to 48 hours after last dose of indomethacin, interference with the oxygen consumption autoregulation mechanisms in the mesenteric circulation, renal effects including decreased GFR, urinary volume, and FENa+, and increased sytemic vascular resistance mean arterial pressure.

Accurate fluid intake and urinary output during therapy is important to prevent fluid overload with dramatic changes in urine output. Decreased urine output is expected and is not a contraindication for further indomethacin therapy, although administration of dose may be deferred if urine output falls to less than 0.5 ml/kg/hr. Fluid intake should normally be reduced during indomethacin treatment in anticipation of decreasing urine output. Volume expansion in response to a decreased urine output is contraindicated and will not induce a diuresis. Co-administration with dopamine at a dose of 2 - 3 mcg/kg/min. may counteract the oliguric effect of indomethacin.

Protocol for use of prostaglandin E₁

Jeffrey L. Segar, MD
Peer Review Status: Internally Peer Reviewed

Indication

An infant suspected of having a ductal-dependent congenital cardiac defect and ductal-dependent pulmonary blood flow should be treated with prostaglandin E₁ because he/she is at risk for progressive hypoxia and metabolic acidosis if the ductus closes. Prostaglandin E₁ will prevent the ductus arteriosus from closing and reestablish ductal patency if closure has already occurred, and thereby increase PaO₂, and mitigate the onset of metabolic acidosis. This drug is indicated for the temporary management of the neonate with ductus-dependent congenital heart disease while awaiting transfer to a tertiary care nursery for evaluation and surgical therapy. It is also used to stabilize a neonate's condition until surgery can be completed.

Patient population

Most often the neonate with ductal-dependent congenital cardiac disease is a full term infant whose size is appropriate or large for gestational age. The drug is indicated for use in the neonate with ductal-dependent pulmonary blood flow, including: pulmonary atresia, tricuspid atresia, Tetralogy of Fallot, and will often improve systemic oxygen saturation in infants with transposition of the great vessels. Note, in infants with obstructive total anomalous pulmonary venous return, a left Æ right shunt via a PDA can decrease systemic blood flow and increase blood flow to the pulmonary bed resulting in pulmonary vascular congestion and worsening of infant’s condition.

Patient identification

The infant should have the following studies performed prior to the initiation of prostaglandin therapy.

• Hyperoxic Challenge Test: Right radial artery blood gases obtained in an FiO₂ of 1.0 (pCO₂ 35-40 torr [normal] and PaO₂ less than 100 torr is consistent with cyanotic congenital heart disease).
• Chest x-ray: Decreased pulmonary vascularity
• Serum glucose: If the neonate is hypoglycemic, treat appropriately and reassess arterial blood gases and pH.
• Hematocrit: Central venous hematocrit of greater than 60% may result in hyperviscosity syndrome (plethora, cyanosis and dyspnea).
• Adequate ventilation: If there is any question as to the adequacy of ventilation, the neonate should be mechanically ventilated and arterial blood gases reassessed.These studies will aid in the identification of the neonate with another etiology for central cyanosis. Only definitive echocardiography and cardiac catheterization will clearly identify infants with ductal dependent pulmonary blood flow.

Administration

Prostaglandin E1 is packaged in a 1 ml ampul of 500 micrograms (0.5 mg). Use one of the following methods to prepare a solution for infusion.

• Dilute one ampul in 500 ml D5W or D10W = 1 mcg/ml (0.001 mg/ml) solution.
  To give 0.05 mcg/kg/min. = 3.0 ml/kg/hr
• [weight (kg) ÷ 10] = # mg PGE1 in 100 ml IVF @ 3 ml/hr = 0.05 mcg/kg/min
• Dilute one vial in 100 ml of D5W or D10W = 5 mcg/ml solution. To give 0.05 mcg/kg/min. = 0.6 ml/kg/hr

Make sure the drug is thoroughly mixed in solution and all lines are purged. Once mixed, the solution is stable for 24 hours. Prostaglandin E1 is infused continuously by pump via a large peripheral vein (preferably not scalp vein) or umbilical ine. There is evidence that doses greater than 0.1 mcg/kg/min are -not more- effective, and may cause an increase in adverse reactions.

Response and duration of action

The neonate generally responds with an increase in PaO2 10-15 minutes after initiation of the drug. Some patients may not respond until several hours of drug infusion have elapsed. The half-life of the drug is one circulation time; therefore, continuous uninterrupted infusion must be maintained. Once the patient responds, the dose can be reduced to one-half or less of the initial effective dose.

Precautions

Monitor respiratory rate, temperature, blood pressure and arterial blood gases and pH at the initiation of and intermittently during infusion.

Adverse reactions

About 20% of infants who receive this drug have one or more adverse reactions. Three common side effects are apnea (12%), fever (14%), and flushing (10%). Non-central nervous system twitching, fever, and peripheral flushing - particularly if given intra-arterially, will usually cease with reduction of the dose by 50%. Apnea is an indication for assisted or mechanical ventilation. A decrease in systolic arterial pressure of greater than 20% is an indication for volume expansion by 10 ml/kg of colloid. Hypoglycemia may develop after several hours of treatment.

This protocol is presented as a suggestion for the use of the drug. Particular questions involving patients should be directed to the Neonatologist (319-356-1616; Beeper 3792) and/or Pediatric Cardiologist (319-356-1616; Beeper 3609) on-call at University Hospitals.