Specific adrenoceptor
The main target organ(s)
Clinical response
α1 (including α1A, α1B, α1D)
Arteries, arterioles, veins; however, α effects predominate over β in splanchnic circulation
Arterial constriction
α2 (including α2A, α2B, α2C)
Gastrointestinal (GI) tract
Cutaneous circulation
Decreased GI tone
Decreased motility
Decreased amount of GI secretions
β1
Heart (β 1>> β 2 in coronary circulation)
Increased heart rate
Augmented myocardial contractility
β2
The vessels of the skeletal muscles
Dilation of the vessels
Coronary arterial bed
Dilation of the vessels
Smooth muscles in the tracheobronchial tree
Relaxation of the smooth muscles
β3
Adipose tissue
Enhancement of lipolysis in adipose tissue, thermogenesis in skeletal muscle
Table 4.2
Myocardial receptors characterized by their properties
Receptor type | Inotropy | Chronotropy | Dromotropy | Lusitropy | Bathmotropy |
|---|---|---|---|---|---|
β 1 | + | + | + | + | + |
M 2 | – | – | – | – | – |
Pure Vasopressors (Pure Vasoconstrictors)
Phenylephrine
Drug Name
Phenylephrine hydrochloride
Class
Alpha-adrenergic agonists
CAS Number
61-76-7
Mechanism of Action
Phenylephrine is a sympathomimetic amine that acts by direct stimulation of peripheral α1-adrenergic receptors. It is used as a bolus or an infusion in acute management of low systemic blood pressure. The vasoconstriction effect of α1 adrenoceptors may result in a reflex bradycardia; although the situation is rarely seen in young children, the patient’s heart rate should be carefully monitored when large doses of phenylephrine are administrated.
Phenylephrine has many indications including these:
The most important indication for pediatric patients is raising SVR in CHD conditions when either ventricle is suffering from an outflow obstruction which is exacerbated with low SVR, such as tetralogy of Fallot (TOF), in which low SVR can cause cyanosis during a “tet spell,” hypertonic cardiomyopathy, etc.
It is also indicated in patients with partial obstruction in systemic to pulmonary shunt or single ventricle patients with pulmonary stenosis to improve oxygenation.
Hypotension during anesthesia.
Septic shock.
Prolongation of the effects of local anesthetics.
Prevention and treatment of nasal congestion.
Hemorrhoids.
Dosing
The common dose of phenylephrine in pediatric patients is as follows: bolus dosing, 0.5–5 μg/kg or higher, and infusion dosing (when frequent bolus doses are needed), 0.02–0.3 μg/kg/min, which should be administrated through a central venous catheter if possible.
Common Adverse Effect of Phenylephrine
Vasoconstriction of peripheral vascular beds, including the skeletal muscle, skin, renal, and mesenteric which can be severe and compromise the blood flow in vital organs, limiting its use in extreme situations
Nausea
Vomiting
Headache
Nervousness
Cautions
Extravasation into skin and subcutaneous tissues is the main caution when administrating phenylephrine; this can result in ischemia, necrosis, and even tissue loss. Also the sulfite in phenylephrine formulations can cause hypersensitivity reactions in susceptible individuals.
Vasopressin
Name of Drug
Vasopressin
Class
Pituitary
CAS Number
11000-17-2
Vasopressin is a vasopressor drug acting through specific vasopressin receptors. Vasopressin should be used after hemodynamic stability and is usually used in vasodilatory shock, usually when other agents are irresponsive (Holmes et al. 2003, 2004; Stahl et al. 2010; Sharawy 2014).The effects of vasopressin in refractory shocks have been studied, and many believe that low-dose vasopressin is a useful drug for septic shocks patients who have already received drugs like norepinephrine infusion (Russell 2011).
Mechanism of Action
Vasopressin is the exogenous antidiuretic hormone (ADH) and as a vasopressor which produces intense vasoconstriction (through V1 receptors); also, it has antidiuretic effects (V2 receptors). When the therapeutic doses of catecholamines are acutely or chronically elevated and, hence, adrenergic receptors mare downregulated, impaired signal transmission in adrenergic receptors occurs, especially when there is concomitant metabolic acidosis; this is why using vasopressin is advantageous in such situations. On the other hand, another potential advantage of vasopressin is that V2 receptors help create vasodilation in order to lessen the end-organ hypoperfusion; often, epinephrine or norepinephrine administration may lead to end-organ hypoperfusion in some of the visceral organs (Holmes et al. 2003, 2004; Meyer et al. 2008).
Indications
Vasopressin has many indications in pediatric population including:
Diabetes insipidus
Polyuria
CPR
Abdominal radiographic procedures
Diagnostic procedures
Gastrointestinal hemorrhage
Vasodilatory shock
Its use in treating refractory vasodilatory shock in pediatric patients with cardiogenic and septic etiologies is gaining day-to-day importance (Biban and Gaffuri 2013; Okamoto et al. 2015). Vasopressin is especially useful in cases of low systemic vascular resistance (SVR) brought on by excessive α-adrenergic blockade, such as with phentolamine or phenoxybenzamine (Motta et al. 2005; Mossad et al. 2008; Gordon 2016).
The usual dose of vasopressin administrated is 0.2–2 milliunits/kg/min infusion, which can be titrated to achieve desired effect; however, the dose should be weaned and discontinued as soon as possible. 4–8 milliunits/kg/min doses have been reported in some clinical trials to treat vasodilatory shock (Choong and Kissoon 2008; Singh et al. 2009).
Adverse effects associated with low doses of vasopressin are infrequent and mild; however, they increase in frequency and severity with higher doses.
Hypertension and bradycardia may occur due to severe vasospasm and the resulting hypertension which induces baroreceptor reflex. Arrhythmia is infrequent. Also, peripheral vasoconstriction may lead to distal limb ischemia. If extravasation occurs, skin necrosis is possible. Hyponatremia is common with vasopressin infusions when prolonged periods of drug infusion are used; therefore, serum sodium should be measured at least daily to prevent this untoward effect. Vasopressin can cause hypersensitivity reactions in susceptible individuals and should be administrated with caution in older children (Sharawy 2014).
Finally, it seems strongly logic to use vasopressin as a rescue therapy and the last–resort treatment in children with refractory shock (unresponsive to norepinephrine and epinephrine); of course, its use should be individualized and with considerations regarding the underlying clinical state (Meyer et al. 2008; Brissaud et al. 2016).
Terlipressin is another analogue of vasopressin with higher selectivity for V1 receptors; also, it has a longer half-life compared to vasopressin; terlipressin is triglycyl lysine vasopressin and is used in norepinephrine-resistant shocks with different ranges of doses varying from 7 mcg/kg twice a day to 2 mcg/kg every 4 h; however, its pharmacology is not well studied in pediatric and neonatal patients, and also, it is not available in some countries; there are still no firm recommendations for using terlipressin in severe shock in pediatric patients (O’Brien et al. 2002; Leone and Martin 2008; Meyer et al. 2011; Biban and Gaffuri 2013).
Inoconstrictors
In evaluation of catecholamines, one should always keep in mind that the density of adrenoceptors and their response to catecholamines are all markedly affected by a number of factors; among them, the two have utmost importance:
Epinephrine
Name of Drug
Epinephrine (Adrenalin)
CAS Number
51-43-4
Drug Group
α- and β-adrenergic receptor agonist
Mechanism of Effect
Epinephrine affects all adrenergic receptors including α1, α2, β1, β2, and β2; also, the clinical effects of epinephrine are similar to the effects of sympathetic stimulation with all of its clinical presentations being seen except for its effects on facial arteries and the effects on sweating; epinephrine is assumed as the most potent α-adrenergic agonist (Cooper 2008; Jentzer et al. 2015).
Low-dose epinephrine infusions affect mainly the β-adrenoceptors. This is why doses of <0.1–0.2 mcg/kg/min are usually considered as “pure” inotropic dose, which could improve pump failure after cardiac surgery. However, with increasing the dose, the vasoconstrictor effects of epinephrine are presented much more (Bangash et al. 2012; Noori and Seri 2012; Jentzer et al. 2015).
Epinephrine affects the smooth muscles of bronchi and pupils and leads to bronchial dilation and iris dilation. Glycogenolysis is speeded up in liver due to epinephrine effects leading to increased blood level of glucose. Epinephrine could induce myocardial ischemia, tachyarrhythmia, pulmonary hypertension, hyperglycemia, and lactic acidosis. Epinephrine compromises hepatic and splanchnic perfusion, lactate clearance, and oxygen exchange. The decrease in hepaticosplanchnic perfusion in addition to increased hepatic metabolic workload, hypermetabolism, impairment of oxygen exchange, glycolysis, and suppression of insulin release are the main etiologic causes for lactic acidosis and hyperglycemia. Also, epinephrine acts as antagonist of histamine (Trappe et al. 2003; Bangash et al. 2012; Bracht et al. 2012).
Indications
Cardiopulmonary resuscitation and rhythm disturbances: they are used to increase coronary perfusion pressure and cerebral perfusion pressure, mainly through α1-adrenergic activity, which increases the diastolic perfusion pressure. However, β-adrenergic activity increases the myocardial load and decreased subendocardial perfusion; so, these effects are not optimal effects; if the patient is in shock due to cardiac problems, epinephrine should be used cautiously due to adverse myocardial effects. Epinephrine is considered as the first-line catecholamine agent which is used in cardiopulmonary resuscitation and, also, in anaphylactic shock (Kee 2003; Bangash et al. 2012; de Caen et al. 2015; Maconochie et al. 2015).
Bronchospasm: it acts as a rapid bronchodilator in acute bronchospasm and bronchial asthma; however, its unwanted effects on the cardiovascular system mandate using selective β2 agonists in such cases.
Anaphylaxis and anaphylactoid reactions: during life-threatening anaphylaxis reactions and emergencies, the drug is used; subcutaneous route is usually used in such circumstances; however, in life-threatening emergencies, cautious intravenous supplements may be considered (Simons and Sampson 2015).
Gastrointestinal and renal bleeding: local intra-arterial administration into the celiac trunk, inferior mesenteric artery, or superior mesenteric artery could be used.
As adjunct to local anesthetics: it could decrease local absorption of the drug.
Other uses: radiation nephritis, control of local skin and/or mucosal bleeding, premature labor, treatment of severe hypoglycemia, as adjuvant to radiocontrast dyes.
Routes of Administration
Epinephrine could be administered through the following routes (Cooper 2008; de Caen et al. 2015; Jentzer et al. 2015):
Intravenous
Intramuscular
Subcutaneous
Infusion through intravenous line or central line
Intra-arterial (very rarely; e.g., in radiographic assessments)
Through endotracheal tube in cardiopulmonary bypass
Intraosseous
Inhalational through pulmonary devices like metered dose inhalers or nebulizers (usually used for children above 4 years)
Local administration in control for mucosal or skin bleeding
Epinephrine Dose in Pediatric Cardiac Surgery
Very low-dose epinephrine is defined as 0.01–0.05 mcg/kg/min. This dose of epinephrine does not raise plasma epinephrine levels significantly in such a way to induce major cardiovascular responses; if any response is seen, it will be predominantly due to β-adrenoceptor effects (Kee 2003; Maslov et al. 2015).
Low-dose epinephrine is considered as infusion between 0.05 and 0.1 mcg/kg/min (Maslov et al. 2015). Low-dose epinephrine causes β2 adrenergic effects (β2 > β1 > α1). The result is decrease in both systemic vascular resistance (SVR) and blood pressure; however, myocardial contractility increases. As mentioned above, low-dose epinephrine infusions are usually considered as “pure” inotropic dose; this dose improves pump failure after cardiac surgery mainly through β-adrenoceptors. Of course, pharmacodynamics studies have demonstrated that heart rate should raise first before any inotropic effect of epinephrine could be exerted (Maslov et al. 2015; Lucas et al. 2016).
Moderate-dose epinephrine infusion is between 0.1 and 0.5 mcg/kg/min, though this dose is not exactly the same in all classifications (Watt et al. 2011). In this dose, α1 effects are much more pronounced than the lower doses.
High-dose epinephrine infusion is between 0.5 and 1 mcg/kg/min. in this higher dose, α1 > β1, β2 leading to increased SVR and increased cardiac index; among the clinical results is significant increase in diastolic blood pressure. Also, systolic, diastolic, and mean arterial blood pressures are elevated. This dose range may lead to increased plasma levels of glucose and lactate (Clutter et al. 1980; Cooper 2008; Jentzer et al. 2015).
Very high-dose epinephrine is when epinephrine infusion dose increases above 1.5 mcg/kg/min; as a result, SVR increases significantly, resulting in significant decrease of cardiac index. Meanwhile, pulmonary vascular resistance and right ventricular afterload are increased. These events lead to increased myocardial oxygen demand due to increased heart rate and stroke work (Maslov et al. 2015).
During cardiac arrest, the doses of epinephrine are needed that vasoconstrictive α-effects predominate, in order to increase diastolic pressure in the root of aorta leading to improved myocardial perfusion pressure. The desired dose of epinephrine in CPR will be intravenous bolus of 0.01–0.03 mg/kg every 3–5 min. It is not recommended to use doses higher than 1 mg in every 3–5 min interval. In refractory bradycardia after cardiac arrest, 0.1–0.2 mcg/kg/min as intravenous infusion could be used. Also, intraosseous dose for pediatric cardiac arrest is 0.1 mg/kg up to 1 mg which could be repeated every 3–5 min. Endotracheal tube administration of epinephrine should be with ten times higher than IV doses (0.1 mg/kg) which could be repeated up to a total dose of 10 mg; the dose could be repeated every 3–5 min during the course of CPR; however, endotracheal dose of epinephrine should be diluted in 5 mL normal saline followed by five manual ventilation maneuvers to augment its absorption (Kleinman et al. 2010; Atkins et al. 2015; de Caen et al. 2015; Maconochie et al. 2015).
Cautions
Epinephrine could lead to dangerous side effects if it is not delivered cautiously; very high blood pressure, myocardial ischemia and chest pain, aortic injures and disruption, or even rupture of cerebral arteries may ensue due to inadvertent injection of the drug, leading to CNS injuries. For inpatients with underlying arrhythmia, hypertension, or hyperthyroidism, more caution is necessary. Patients undergoing general anesthesia with volatile agents are at risk of arrhythmias. In patients receiving MAO inhibitors, simultaneous administration of epinephrine needs extreme caution. Acute angle glaucoma may worsen due to epinephrine. However, in life-threatening conditions, there is no absolute contraindication.
Dopamine
Name of Drug
Dopamine hydrochloride
CAS Number
62-31-7
Drug Group
Selective agonist of β-1 adrenergic receptors
Mechanism of Effect
Dopamine is a natural catecholamine which is produced in the following famous chain:
L-Phenylalanine is converted to L-tyrosine, and then it is converted to L-DOPA (L-3,4-dihydroxyphenylalanine). Then DOPA is changed to dopamine through the enzyme “DOPA decarboxylase.”
Dopamine is one of the precursors of norepinephrine. Also, dopamine acts as a neurotransmitter in some of the sympathetic pathways. Besides, dopamine is a major neurotransmitter in some parts of the CNS like nigrostriatal pathway.
Dopamine has both positive chronotropic and inotropic effects on myocardium; so, it increases heart rate and myocardial contractility. These effects of dopamine are done through two mechanisms:
Direct effect which is produced by agonistic effects of dopamine on beta adrenoceptors
Indirect effect which is produced due to the effect of dopamine in releasing norepinephrine from its storage sites in sympathetic nerve endings
Clinical Effects of Dopamine
Often, dopamine is clinically considered as a vasoconstrictor and as an inotrope (i.e., inoconstrictor); however, the effects of dopamine on alpha- and beta-adrenergic receptors are weaker than epinephrine or norepinephrine. The clinical effects of dopamine are highly dose dependent, and also, there is interindividual variability in clinical response. Besides, in different clinical conditions of the same patient, there may be altered responses to dopamine. Keeping these in mind, we may classify the effects of dopamine based on the dose (Kee 2003; Trappe et al. 2003; Cooper 2008; Bangash et al. 2012; Bracht et al. 2012):
Low-dose dopamine (0.5–2 μg/kg/min): it causes vasodilation which seems to be due to the selective effects of the drug on dopamine receptors which are different from its effects on α- and β-adrenoceptors (mainly on mesenteric, renal, intracerebral, and coronary vascular beds); haloperidol acts as antagonist to these receptors. Increased glomerular filtration rate, increased renal blood flow, increased renal excretion of sodium, and increased urine flow are among the main results of this dopamine dose; often, increased renal blood flow does not affect urine osmolality. However, the so-called renal-dose dopamine which is the same as low-dose dopamine is not supported by evidence for renal protection. Total peripheral vascular resistance is usually not altered so much in this dose (0.5–2 μg/kg/min) because it would be raised by alpha activity.
Medium-dose dopamine (2–10 μg/kg/min): it mainly stimulates β1 adrenoceptors and increases myocardial contractility. Also, this dose augments stimulation of the sinoatrial node and increases impulse conduction in myocardial tissue. β2 adrenoceptors, which cause peripheral vasodilation, are usually not stimulated by this dose (i.e. 2–10 μg/kg/min). However, the degree of increased myocardial oxygen consumption by dopamine is less than isoproterenol. Also, dopamine increases systolic blood pressure and pulse pressure while diastolic blood pressure is not much affected. As mentioned, in low to moderate doses of dopamine, total peripheral vascular resistance is usually not altered so much (because it would be raised by alpha activity). So, as a result of relatively constant vascular resistance and increased cardiac output, perfusion in the vascular bed is increased with 2–10 μg/kg/min dose. Often, tachyarrhythmia is not a frequent result of dopamine use.
High-dose dopamine (10–20 μg/kg/min): the effects of dopamine in these doses are mainly α-adrenoceptor stimulation; the clinical result is vasoconstriction and increased blood pressure. Vasoconstrictive effect is first seen in muscular arterial tone; however, renal and mesenteric vessels are affected afterwards and with increased dose of drug. Very high dopamine doses (especially doses above 20 μg/kg/min) may lead to ischemia in the aforementioned organs, including limbs; so, doses above 20 μg/kg/min may compromise the circulation of the limbs, and we may consider the effects of this very high dose as similar to the effects of norepinephrine.
Dopaminergic activity; its effect on the immunologic and neurohormonal systems
There is increasing evidence that there are very important interactions between dopaminergic system and many aspects of the neurohormonal system including a decline in secretion of prolactin, thyroid, and growth hormones and increased synthesis of the glucocorticoid hormones; these effects are especially important in the critically ill and septic patients (Van den Berghe and de Zegher 1996; Bailey and Burchett 1997).
Besides, there are great interactions between dopamine and the immunologic system, both in health and disease. In fact, dopamine could play a crucial role in modulation of the immunologic and inflammatory response. These immunomodulatory effects of dopamine are dose dependent and mediated though different dopamine receptors:
The first family of dopaminergic-like receptors is known as D1 receptors and includes D1 and D5; and the second family of dopaminergic-like receptors is known as D2 receptors and includes D2, D3, and D4; besides, these immunomodulatory effects are mediated though α- and β-adrenergic receptors (Elenkov et al. 2000; Beck et al. 2004; Franz et al. 2015; Levite 2016).
Dopamine affects the cytokine network, leading to decreased expression of adhesion molecules, suppression of the production trend in cytokine and chemokine network, decreased potency of neutrophil in producing chemotaxis, and impaired proliferation of T-cell population (Elenkov et al. 2000; Beck et al. 2004; Franz et al. 2015; Levite 2016).
Dopamine receptors are expressed in T lymphocytes leading to modulation of this cell population; this effect is mediated through both the dopaminergic D1 receptors (D1/D5) and the dopaminergic D2 receptors (D2/D3/D4) (Elenkov et al. 2000; Zhao et al. 2013; Franz et al. 2015).
The cytotoxic effects of natural killer cells are highly affected by dopamine receptors: D1 receptors (D1/D5) facilitate the activity of natural killer cells; however, D2 receptors (D2/D3/D4) suppress the activity of natural killer cells (Zhao et al. 2013; Franz et al. 2015).
Dendritic cells (DCs) are a main part of innate immunity system; also they act as a very important linker between innate and adaptive immune system with a very crucial role in activation of the adaptive immune system. DCs affect the whole dopaminergic system in nearly all aspects which yields to increased production and storage of dopamine; in turn, DCs stimulate the D1 and D2 receptors in an autocrine manner (Prado et al. 2013; Pacheco et al. 2014; Franz et al. 2015; Herrera et al. 2015; Levite 2016).
Dopamine could augment differentiation of CD4 (+) T cells to T helper 1, T helper 2, and T helper 17 cell lines; these are inflammatory T cells (Prado et al. 2013; Franz et al. 2015; Herrera et al. 2015; Levite 2016).
On the other hand, regulatory T cells may lead to release of large amounts of dopamine which can also release high amounts of dopamine; then, dopamine, in an autocrine/paracrine manner, through dopamine receptors, suppresses the effects of regulatory T cells; this effect of dopamine through regulatory T cells is in favor of inflammatory process and autoimmunity (Pacheco et al. 2014; Franz et al. 2015; Herrera et al. 2015; CID = 681 2016; Levite 2016) (Table 4.3).
Table 4.3
A summary of the effects of dopamine stimulation with different doses
Dose of dopamine
Type of affected receptor(s)
α1 adrenoceptor
α2 adrenoceptor
β1 adrenoceptor
β2 adrenoceptor
Dopamine 1 receptor (D1)
Dopamine 2 receptor (D2)
0.5–2 μg/kg/min
0
0
+
0
+++
+++
2–10 μg/kg/min
+
+
+++
+++
++++
++++
10–20 μg/kg/min
+++
+
+++
+
++++
++++
Time of Effect
During the first 5 min after commencing dopamine infusion, its effects are started; meanwhile, the plasma half-life of dopamine is about 2 min; so, it takes less than 10 min for systemic effects of dopamine to be disappeared. In patients using monoamine oxidase (MAO) inhibitors, the drug effect may be as long as 1 h, which mandates careful attention.
Indications
- 1.
Shock: to increase cardiac output, blood pressure, and urinary flow; of course, volume replacement should be done first. Also, dopamine is used to increase systemic vascular resistance in these patients.
- 2.
Acute renal failure: though doses less than 5 μg/kg/min affect the dopaminergic receptors and may increase renal and mesenteric perfusion, no improvements in glomerular filtration rate (GFR) are seen; no significant evidence is available that dopamine could improve oliguric state in the critically ill patients.
- 3.
Hepatorenal syndrome: as part of the therapeutic protocol in such patients; however, long-term treatment is not associated with significant effects.
- 4.
Cirrhosis: as part of the therapeutic regime is used; no proof for its long-term effects.
- 5.
Cardiopulmonary resuscitation: as part of advanced cardiac life support (ACLS) to increase cardiac output and blood pressure.
- 6.
Heart failure: in refractory cases with no significant improvement with cardiac glycosides and diuretics, dopamine could be used in short term to increase cardiac output and blood pressure.
Dopamine Dose and Administration
Dopamine is usually administrated by intravenous infusion (bolus administration should be avoided); however, in certain situations, where intravenous infusion is not possible, it might be administrated through intraosseous infusion.
The intravenous infusion of dopamine should be done through central or at least large peripheral veins, preferably the antecubital vein; also, it is better to use an infusion pump to control the rate of flow; the dorsal veins of hand and ankle can increase the risk of extravasations and therefore should be avoided; usually, DW5 % is used to dilute dopamine and achieve subsequent concentrations of 400, 800, 1600, and 3200 mcg/mL of dopamine. The 3200 mcg/mL concentration is used when higher concentrations are needed in patients with fluid restriction (Kee 2003; Jentzer et al. 2015; CID = 681 2016; Rizza et al. 2016).
Specific Considerations for Children
Dopamine can be used in any age, the rate of administration is different in every individual, and it should be titrated to reach the desired response. The usual rate of administration in pediatric shock and CPR, and as an inotropic agent to assist weaning from cardiopulmonary bypass in children, and in the early postoperative period is starting with 2–5 mcg/kg/min and then increasing the dose 1–4 mcg/kg/min every 10–30 min to achieve the optimal response. Most patients are controlled with 5–15 mcg/kg/min. infusion rates higher than 20 mcg/kg/min which can cause excessive vasoconstriction.
Clearance of dopamine is not predictable in young children, especially neonates, and it can be up to two times higher in children younger than 2 years old. Neonates are also more sensitive to vasoconstrictor properties of dopamine. Occasionally doses as high as 50 mcg/kg/min are needed for younger children. Some clinicians avoid dopamine due to its potential to cross the blood–brain barrier and suppress pituitary hormones like thyroid-releasing hormone, in pediatric patients. These potential adverse effects are not seen with other natural or synthetic catecholamines.
Common Adverse Effects
Tachycardia, angina, palpitation, vasoconstriction, hypotension, dyspnea, nausea, vomiting, and headaches.
Warnings and Contraindications
In patients who have been previously (within 2–3 weeks of dopamine administrations) treated with MAOIs, dopamine dose should be reduced.
Patient’s plasma volume and electrolytes should be monitored to avoid overhydration while administrating IV fluids.
Sensitive reactions are probable in patients allergic to sulfite (present in some formulations) or corn products (present in dextrose IV solutions)
Dopamine is contraindicated in patients with pheochromocytoma or uncorrected tachyarrhythmias or VF.
General Precautions
The patients’ general condition, ECG, BP, and urine flow, and also preferably cardiac output and pulmonary wedge pressure should be monitored carefully before and during the treatment with dopamine to avoid the incidence or exacerbation of any of the following conditions: extravasation; hypovolemia; hypoxia, hypercapnia, and acidosis; vasoconstriction; hypotension; occlusive vascular disease; ventricular arrhythmias; ischemic heart disease; and diabetes mellitus (caution in administrating dextrose).
In order to discontinue dopamine infusion, dose of dopamine should be decreased gradually while expanding blood volume with IV fluids to prevent a recurrence of hypotension.
Norepinephrine
Name of Drug
Norepinephrine bitartrate (Levophed)
Class
Alpha- and beta-adrenergic agonists
CAS Number
69815-49-2
Norepinephrine is a natural occurring catecholamine, and it is mainly released by the postganglionic adrenergic nerve endings and the adrenal medulla (10–20 %). Norepinephrine, like epinephrine, works by stimulating the β1 adrenoceptors on the heart and therefore increasing the myocardial contractility.
The variation in the clinical use of epinephrine and norepinephrine is due to their difference in peripheral function. Norepinephrine is a potent α1 agonist with little to no effects on β2 receptors responsible for vasodilatation; therefore, it increases the SVR and blood pressure even with low doses. Cardiac output is usually decreased or unchanged, and heart rate may be reduced as a result of reflex increase in vagal tone. Both drugs can cause hyperglycemia in prolonged infusions, with norepinephrine causing these effects at much higher doses than epinephrine.
Indications
The main indication of epinephrine is in treatment of disease states when other vasopressor agents fail and there is a need for a very potent vasoconstrictor; the main examples are refractory shock due to any cause or vasoplegia syndrome (including vasoplegia syndrome after cardiopulmonary bypass); the following is a list of indications for norepinephrine use (De Backer et al. 2010; Mossad et al. 2011; Bangash et al. 2012; Vasu et al. 2012; Mehta et al. 2013; Rizza et al. 2016; Rossano et al. 2016):
Shock: for vasoconstriction and cardiac stimulation in the treatment of shock that persists after adequate fluid volume replacement and in cases of profound vasodilatory shock unresponsive to high doses of dopamine or dobutamine, such as sepsis in neonates.
Anaphylactic shock: vasopressor agents, such as norepinephrine, can be used for maintaining blood pressure in patients with anaphylactic shock, but epinephrine is the drug of choice in these situations.
Myocardial infarction: to treat the hypotension in selected cases.
CPR: may be used for ACLS when severe hypotension (e.g., SBP <70 mmHg) and low total peripheral resistance persist with less potent drugs.
Hypotension during anesthesia: is among a list of alternatives; however, agents like intravenous ephedrine or phenylephrine or other vasopressors are used much more commonly.
Adjunct to local anesthetics: to decrease the rate of vascular absorption of the anesthetic, hence increasing the duration of anesthesia; however, epinephrine is used much more commonly for this purpose.
GI hemorrhage: intraperitoneally or via a nasogastric tube as a hemostatic agent for severe upper GI bleeding.
Pericardial tamponade to temporarily increase cardiac filling pressure and cardiac output.
Dose and Administration
Administration is done by intravenous (IV) infusion using an infusion pump or other apparatus to control the rate of flow and into the antecubital vein of the arm or femoral vein. Norepinephrine should not be administered in the same IV line as alkaline solutions, which may inactivate the drug. Extravasation may result in local necrosis and must be carefully avoided. It is suggested to change the injection site periodically in prolonged therapy.
Dose range of norepinephrine infusion in pediatric cardiac patients varies from 0.02 to 0.2 mcg/kg/min. And it is better to be administered in the lowest effective dosage for the shortest possible time.
In shock usually a dose of 2 mcg/min or, alternatively, 2 mcg/m2 per minute is administrated. In Pediatric Advanced Life Support (PALS) during CPR, 0.1–2 mcg/kg/min is infused intravenously as an adjunct to therapy until reaching the optimum blood pressure and perfusion (De Backer et al. 2010; Mossad et al. 2011; Vasu et al. 2012; Rossano et al. 2016).
Warnings and Contraindications
Norepinephrine is contraindicated during anesthesia with cyclopropane or halogenated hydrocarbon general anesthetics, though they are rarely used in the current era. Also use in fingers, toes, ears, nose, or genitalia in conjunction to local anesthetics is contraindicated.
The following conditions should be thoroughly monitored in patients treated with norepinephrine: hypovolemia, as vasopressor therapy is not a substitute for replacement of blood, plasma, fluids, and/or electrolytes; hypoxia, hypercapnia, and acidosis; extravasation (injection into leg veins should be avoided, especially in geriatric patients or those with occlusive vascular diseases, arteriosclerosis, diabetes mellitus, or Buerger’s disease); hypertensive or hyperthyroid patients (increased risk of adverse reactions due to hypersensitivity to this drug); peripheral or mesenteric vascular thrombosis; and sensitivity reactions (in sulfite-sensitive patients because the formulation contains sulfites).
General Precautions
The following are the main precautions in using norepinephrine (De Backer et al. 2010; Mossad et al. 2011; Bangash et al. 2012; Vasu et al. 2012; Mehta et al. 2013; Rizza et al. 2016; Rossano et al. 2016):
Prolonged administration: as it may cause decreased cardiac output, edema, hemorrhage, focal myocarditis, subpericardial hemorrhage, necrosis of the intestine, or hepatic and renal necrosis which is seen mostly in patients with severe shock and can be due to the shock itself.
Cardiovascular and renal effects: severe vasoconstriction and limiting the blood flow in vital organs.
Increases myocardial oxygen consumption and the work of the heart.
Venous return to the heart may be reduced due to increased peripheral vascular resistance, which can ultimately reduce cardiac output.
Arrhythmias: especially likely to occur in patients with acute MI, hypoxia, or hypercapnia or those receiving other drugs increasing cardiac irritability such as cyclopropane or halogenated hydrocarbon general anesthetics.
Common adverse effects: dizziness, tremor, respiratory difficulty, headaches (Table 4.4).
Table 4.4
A summary of the main vasopressor agents
Drug | Dose | Receptors | Inotropy | HRa | SVR | PVR | Renal vascular resistance | Half- life | Adverse effects |
|---|---|---|---|---|---|---|---|---|---|
Epinephrine | Cardiac arrest: Children: IV bolus: 0.01 mg/kg every 3–5 min Low cardiac output: Continuous IV infusion: 0.01–1 μg/kg/min | Lower doses: | <2 min | Tachyarrhythmias If extravasation occurs, skin necrosis is possible | |||||
β1,β2 > α1 | + | + | 0, – | 0, – | – | ||||
Higher doses: | |||||||||
α1 > β1,β2 | + | + | + | + | + | ||||
Norepinephrine | Continuous IV infusion: 0.05–0.3 μg/kg/min (maximum dose: 2 μg/kg/min) | α1 > β1,β2 | + | + | + | + | − | <2 min | Hypertension Bradycardia Myocardial ischemia If extravasation occurs, skin necrosis is possible |
Dopamine | Continuous IV infusion: | 2 min | Hypertension, tachyarrhythmias | ||||||
2–5 μg/kg/min | DA1, DA2 | 0 | 0 | 0 | 0 | − | |||
5–10 μg/kg/min | β1,β2 > α1 | + | + | 0, − | 0 | 0 | |||
10–20 μg/kg/min | α1 > β1,β2 | + | + | + | + | + | |||
Dobutamine | Continuous IV infusion: 2–20 μg/kg/min | β1 > α1,β2 | + | + | − | − | 0 | 2 min | Tachyarrhythmias |
Isoproterenol | Continuous IV infusion: 0.01–0.2 μg/kg/min | β1,β2 | + | + | − | − | − | 8–50 min | Tachyarrhythmias |
Calcium Chloride | 5–10 mg/kg IV bolus; 10 mg/kg/h infusion 20 mg/kg intracardiac (in ventricular cavity) | Contractile proteins | + | 0,− | + | 0,+ | 0 | N/A | Hypertension |
Milrinone | Continuous IV infusion: 0.25–0.75 μg/kg/min | Phosphodiesterase III, inhibitor/↑ cAMP | + | + | − | − | − | Infants: 3.15 0 2 h Children: 1.86 0 2 h | Hypotension, ventricular arrhythmias, headache |
Nesiritide | Continuous I.V. Infusion: 0.01 μg/kg/min; if necessary, titrate by 0.005 μg/kg/min every 3 h to maximum of 0.03 μg/kg/minb | B-Natriuretic peptide | 0 | 0 | − | − | + | 60 min | Hypotension, increased levels of serum creatinine |
Levosimendan | 6–12 μg/kg load; 0.05–0.1 μg/kg/min | Troponin C, increasing Ca2+sensitivity; ATP-sensitive K+ channels for vasodilation | + | 0 | − | − | − | 1 h | Hypotension, tachyarrhythmias, nausea, headache |
Digoxin | Oral: 5–15 mcg/kg/d divided every 12 h IV: 4–12 mcg/kg/day divided every 12 h | Inhibition of the Na+/K+ ATPase in myocardium | + | − | − | − | − | Infants: 18–25 h Children: 35 h | Nausea and vomiting Dizziness, headache, dysrhythmia |
Phenylephrine | Bolus intravenous dose: 5–20 mcg/kg which could be repeated every 10–20 min Intravenous infusion dose: 0.1–0.5 mcg/kg/min Increase/decrease rate of infusion by minimum of 10 mcg/min at intervals no longer than Q 15 min Titration parameter: MAP; SBP adjusted for age | Selective α1 agonist | 0/+ | 0/− May decrease heart rate if blood pressure goes very high | +++ | 0/+ | ++ | 5 min | Bradycardia, arrhythmia, myocardial ischemia If extravasation occurs, skin necrosis is possible |
Vasopressin | 0.04 units/min | Agonist of vasopressin 1 (V1) receptors | 0 | 0 | + | 0 | 10–30 min | Hypertension Bradycardia Arrhythmia Vasoconstriction Distal limb ischemia If extravasation occurs, skin necrosis is possible |
Inodilators (Mainly Milrinone, Dobutamine, and Levosimendan)
The inodilators are primarily milrinone, dobutamine, and levosimendan. A summary of their characteristics could be found in Table 4.5.
Table 4.5
A summary and comparison between the main inodilators regarding their pharmacological properties in pediatrics
Drug | Dose | HR | MAP | PCWP | CO | SVR | Adverse effects |
|---|---|---|---|---|---|---|---|
Milrinone | 0.25–0.75 mcg/kg/min Increase/decrease by minimum of 0.125 mcg/kg/min at intervals no longer than Q 6 h Parameters for titration of drug: blood pressure; CO; CI | 0/+ | 0/− | − | + | − | Arrhythmia, thrombocytopenia, myocardial ischemia, hypotension/vasodilation No increase in myocardial oxygen demand |
Dobutamine | 2.5–20 mcg/kg/min Increase/decrease by 1 mcg/kg/min at intervals no longer than Q 30 min Parameters for titration of drug: blood pressure; CO; CI | 0/+ | 0 | − | + | − | Arrhythmia may potentiate hypokalemia, increases myocardial oxygen demand, and so may lead to myocardial ischemia and hypotension/vasodilation |
Levosimendan | Loading dose: 6–12 μg/kg over 10 min and then intravenous infusion of 0.05–0.2 μg/kg/min | 0/+ | 0/− | − | + | Headache and/or hypotension may be induced due to vasodilatory effects of drug No risk of arrhythmia No renal or hepatic dose adjustment needed No increase in myocardial oxygen demand |
Milrinone
Name of Drug
Milrinone lactate
CAS Number
78415-72-2
Drug Group
Cardiotonic drug; phosphodiesterase III inhibitor
Mechanism of Effect
Milrinone is a positive inotropic agent and an arterial dilator with weak chronotropic effects; the drug mechanisms are totally different from catecholamine agents. Due to its effects, milrinone is commonly known as an “inodilator”; its mechanism of action is through inhibition of phosphodiesterase (PDE) III isoenzyme in cardiomyocytes and vascular smooth muscle cells; the action of PDE III is to degrade cAMP, and when it is inhibited, intracellular cAMP levels are peaked up which, in turn, leads to increased activation of protein kinase A (PKA). With increased action of PKA, many cellular structures of cardiomyocytes like calcium channels and contractile elements are activated. One of the most important roles of cAMP is to activate protein kinase A (PKA)-mediated phosphorylation of multiple target proteins (Knight and Yan 2012; Ferrer-Barba et al. 2016).
PDE III is one subfamily of the great family of PDEs; there are 11 subfamilies of PDEs; among them, 6 subfamilies function inside cardiac myocytes. One of the main roles of PDE family is to modulate the intracellular cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP), in order to regulate the dynamic interactions between PDEs, cardiac β-adrenergic, PKA, and the process of “synthesis and hydrolysis” of cAMP and cGMP; these are elements of myocardial cells and the contractile processes; more details could be found in Chap. 2 “Cardiovascular Physiology” (Yan et al. 2007; Zaccolo and Movsesian 2007; Miller and Yan 2010; Zhao et al. 2015, 2016).
In smooth muscle cells of the arterial system, PKA leads to relaxation of the vessel walls. However, milrinone does not affect beta-adrenergic activity nor it blocks the activity of Na/K ATPase activity like cardiac glycosides. The positive inotropic effects of milrinone are presented as augmented myocardial contractility and improved Frank–Starling curve in patients with perioperative low cardiac output state. In addition to augmentation of systolic function, milrinone improves diastolic relaxation of the myocardial tissue, leading to improved diastolic function. The inodilator effects of milrinone are seen when the plasma level of the drug is in the range of 100–300 nanogram/mL (Begum et al. 2011; Knight and Yan 2012; Majure et al. 2013; Brunner et al. 2014; Bianchi et al. 2015; Ferrer-Barba et al. 2016; Gist et al. 2016).
Indications
Milrinone is primarily used for the following uses:
Perioperative low cardiac output state (LCOS), including systolic and/or diastolic dysfunction of the myocardial tissue.
In heart failure patients (including cardiogenic shock), milrinone is used for acute term treatment; however, its effectiveness in long-term treatment of heart failure is not confirmed yet.
Pulmonary hypertension, especially in cases of perioperative pulmonary hypertensive crisis (some studies have demonstrated inhalational use as the method of choice for such patients).
Drug Dose
Loading dose: 25–75 μg/kg (in patients undergoing cardiopulmonary bypass, this loading dose is often administered as a bolus dose during CPB); however, if the patient is not under cardiopulmonary bypass, this loading dose should be administered intravenously in 10–60 min, with vigilant control of blood pressure.
Maintenance dose: 0.25–0.75 μg/kg/min as intravenous continuous infusion, the loading dose can be avoided to prevent the initial hypotension, and the treatment can begin with the infusion, recognizing that therapeutic plasma levels will not be achieved for several hours.
These doses lead to the desired plasma level of 100–300 nanogram/mL; however, in patients with acute kidney injury, there should be dose modification, since milrinone is metabolized mainly through kidneys (Gist et al. 2016).
Routes of Administration
Milrinone is infused primarily through intravenous route, either peripheral or central lines; however, during cardiopulmonary bypass, bolus dose of drug could be administered through the ports of bypass circuit. Some studies have demonstrated these alternative routes; their efficacy is to be determined:
Intraosseous (e.g., during cardiopulmonary resuscitation when there is no intravenous line)
Inhalational route, especially in pulmonary hypertension crisis and cardiac transplant patient which is selectively absorbed by the pulmonary vascular system, so preventing hypotension (Brunner et al. 2014; Ventetuolo and Klinger 2014)
Oral route which is not a routine method since it is claimed to increase morbidity (Ogawa et al. 2014)
The primary bolus dose and then the maintenance dose of milrinone could be diluted with these solutions:
Half saline
Normal saline
Normal saline with 5 % dextrose
Adverse Effects and Pharmaceutical Precautions:
One of the main contraindications of milrinone is hypersensitivity to drug or any of its formulations.
Obstructive valve lesions, especially diseases like hypertrophic subaortic stenosis, aortic valve stenosis, or pulmonary valve stenosis; in such patients, pending on the severity of stenosis, milrinone may be prohibited or, at least, its use must be with strict caution.
Decreased impulse delay in atrioventricular (AV) node which might lead to increased ventricular response in patients with underlying atrial flutter or atrial fibrillation; it is recommended to start cardiac glycosides before milrinone in these patients (Fleming et al. 2008); also, it has been demonstrated that in congenital heart surgery, milrinone is “an independent risk factor for clinically significant early postoperative tachyarrhythmias” (Smith et al. 2011).
Currently, there is not enough data to support intravenous or oral administration of milrinone for periods more than 48 h; overwhelming intracellular accumulation of cAMP has been proposed as the underlying mechanism for such untoward effects; it might lead to arrhythmias.
In patients on diuretics, adding milrinone may lead to increased renal perfusion and potential electrolyte abnormalities.
Decreased ventricular filling pressures may result in severe hypotension which mandates hemodynamic vigilance while starting the drug.
Dobutamine
Mechanism of Action
Dobutamine, which is a synthetic congener of dopamine, mainly acts as a pure positive inotropic agent through adrenergic receptors. It has no effect on DA receptors or the release of norepinephrine from nerve endings. Dobutamine mainly targets β1 receptors and its effects on β2 or α1 receptors are less pronounced. Dobutamine produces a reduction in systemic vascular resistance with only a modest increase in heart rate and blood pressure, which is its most important advantage over dopamine and can be beneficial in patients with ventricular dysfunction.
Indications
Indicated in cardiac decompensation and shock, acute heart failure, low cardiac output state after open heart surgery, neonates with asphyxia, myocarditis, MI, and after open heart surgery.
Dosage
Given as continuous IV infusion in dose of 2–20 mcg/kg/min. Doses more than 20 mcg/kg per minute may produce tachycardia and ventricular ectopy and could induce or exacerbate myocardial ischemia. The concentration used is individualized depending on each patients’ drug and fluid requirements but should not exceed 5000 mcg/mL (=5 mg/mL). Infusion of dobutamine should be gradually tapered after 48–72 h of administration. In patients with hypotension, dopamine or noradrenaline infusion may be used concomitantly with dobutamine.
Side Effects
Ectopic heartbeats, increased heart rate, elevations in BP, hypotension, phlebitis, local inflammatory changes
Contraindications
Contraindicated in obstructive lesions of the heart, cardiac arrhythmias. Hypovolemia must be corrected prior to dobutamine administration. Compared with milrinone, dobutamine shows more profound decrease in left ventricular filling pressures and vascular resistance than the phosphodiesterase inhibitors and is more likely to increase heart rate. When compared to isoproterenol, dobutamine causes less improvement in the automaticity of the sinoatrial (SA) node (Kee 2003; Holmes 2005; Noori and Seri 2012; Jentzer et al. 2015; Rossano et al. 2016).
Levosimendan
Levosimendan is a myocyte calcium sensitizer which is used mainly for treatment of acute decompensated heart failure and/or low cardiac output states in some countries. However, in a number of other countries including the USA, levosimendan is not licensed. Also, a number of trials have been done in pediatric patients demonstrating its efficacy in pediatric congenital heart disease. Its mechanism of action is through increasing myocyte calcium sensitivity by attaching to cardiac troponin C (TnC); this effect is mediated through a calcium-dependent mechanism; but its vasodilatory effects are mediated through opening ATP-sensitive potassium channels; due to these mechanisms, levosimendan does not increase myocardial oxygen demand; instead, it has cardioprotective effects through activation of ATP-sensitive K channels in the mitochondria.
Levosimendan needs no renal or hepatic dose adjustment. Its main complications include headache and/or hypotension due to vasodilatory effects of drug; however, there is no risk of arrhythmia.
The loading dose of levosimendan is 6–12 μg/kg administered intravenously over 10 min followed by continuous intravenous infusion of 0.05–0.2 μg/kg/min; time to start of effect is 5 min, with peak effects being observed in 10–30 min; the time duration of levosimendan effects is about 1–2 h; the infusion should be continued up to 24 h.
Levosimendan may decrease the mortality rate in adult patients; however, the data in pediatric patients are not enough yet (Mebazaa et al. 2007; Landoni et al. 2012; Lechner et al. 2012; Papp et al. 2012; Nieminen et al. 2013; Li and Hwang 2015; Silvetti et al. 2015; Ferrer-Barba et al. 2016; Kushwah et al. 2016; Rizza et al. 2016).
Pure Vasodilators
Nitroglycerin
Nitroglycerin (NTG) and nitroprusside are nitric oxide (NO) donors; however, NTG is predominantly a venodilator, while nitroprusside is a preferential arterial dilator. Besides, the release of NO after NTG administration is mediated through enzymatic pathways. Venodilation due to NTG leads to decrease in preload which decreases in turn the myocardial wall stress; the final result is improved oxygen balance of the myocardial tissue leading to improved myocardial function. Another beneficial effect of NTG is coronary vasodilation. Therapeutic dose of NTG is 0.5–5 μg/kg/min. However, doses from 0.5 to 2 μg/kg/min lead to venodilation, while doses from 2 to 5 μg/kg/min lead to improved cardiac index and decreased pulmonary and systemic blood pressure. Dose titration is based on clinical response (Hari and Sinha 2011).
Hydralazine
Hydralazine is an antihypertensive drug. It lowers blood pressure with a peripheral vasodilating effect, brought on by interfering with the calcium flow in vascular smooth muscle. Hydralazine effect on peripheral vascular resistance is more pronounced in arterioles as opposed to veins; it decreases diastolic blood pressure more than systolic and leads to an increase in heart rate and stroke volume and cardiac output. Hydralazine has an increasing effect on renal and cerebral blood flow.
In pediatric patients, hydralazine is used as an oral antihypertensive agent, when BP is not sufficiently controlled by first-line antihypertensive drugs. The common oral dose in hypertension is 0.75 mg/kg daily (or 25 mg/m2) in 4 divided doses and can be increased gradually up to 7.5 mg/kg daily (or 200 mg daily). It can also be used parenterally in severe hypertension. In this case, 0.2–0.6 mg/kg hydralazine is administrated IV or IM and can be repeated every 4 h. Hydralazine is contraindicated in patients with mitral valvular rheumatic heart disease and CAD. It can cause pyridoxine insufficiency and peripheral neuritis and blood dyscrasias. Patients CBC and neurological symptoms should be monitored during treatment (Hari and Sinha 2011; Watt et al. 2011; Ostrye et al. 2014; Flynn et al. 2016).
Alprostadil
Alprostadil (prostaglandin E1) has various pharmacological effects including vasodilation, stimulation of smooth muscle contraction in intestine and uterus, inhibition of platelet aggregation, and so on. Its vasodilatory effect is shown with doses of 1–10 mcg/kg and can reduce blood pressure and, in reflex, increase cardiac output and heart rate.
Since smooth muscles in ductus arteriosus are especially sensitive to alprostadil, and based on animal studies, there are evidence that alprostadil can reopen closing ductus in newborns; the drug has been investigated in infants with congenital defects with restricted pulmonary or systemic blood flow who depend on a patent ductus arteriosus for sufficient oxygenation and perfusion.
In such pediatric patients, alprostadil infusion was associated with at least a 10 torr increase in blood pO2 (mean increase about 14 torr and mean increase in oxygen saturation about 23 %) in about 50 % of the patients. Patients with low pretreatment blood pO2 who were 4 days old or less seem to have the best response to alprostadil.
Alprostadil can improve acidosis in patients with restricted systemic blood flow. It can also increase systemic blood pressure and decrease the ratio of pulmonary artery pressure to aortic pressure.
Alprostadil is administrated as intravenous or intra-arterial infusion, and the common dose of this drug in patients with ductus arteriosus-dependent congenital heart disease is described here.
In neonates, 0.05–0.1 mcg/kg/min is the starting dose which can be increased gradually to ≤0.4 mcg/kg/min. After therapeutic response achieved, the dosage can be reduced for maintenance from 0.1 downward in a stepwise method, 0.05, 0.025, and finally to 0.01 mcg/kg/min, until lowest effective dose is achieved. The treatment should be continued until surgical repair is complete (usually ≤24–48 h). Arterial pressure should be monitored intermittently, and the infusion rate should be decreased immediately if the pressure drops significantly. Response can be monitored by measuring blood oxygenation or pH (Carroll et al. 2006; Cuthbert 2011; Strobel and Lu le 2015; Lakshminrusimha et al. 2016).
Sodium Nitroprusside
Sodium nitroprusside (SNP) like nitroglycerin is a nitric oxide (NO) donor. Inside the tissues, SNP reacts with physiologic sulfhydryl groups, and the final result is release of NO which in turn increases tissue levels of cGMP, especially in the arterial and venous system; the final result would be smooth muscle relaxation in the walls of the arterial and venous vessels. Physiologically speaking, SNP decreases afterload of left ventricle leading to improved cardiac output, though some degrees of hypotension occur; however, the improved cardiac output, especially in patients with depressed cardiac function, compensates for the hypotension, unless there is profound preexisting hypovolemia or the patient has underlying obstructive diseases like hypertrophic obstructive cardiomyopathy, aortic stenosis, or mitral stenosis (Friederich and Butterworth 1995; Moffett and Price 2008; Thomas et al. 2009).
There is a major concern for SNP toxicity in long-term or large dose infusions; reaction of SNP with oxyhemoglobin leads to formation of methemoglobin, with its final by-product, cyanide anions. Cyanide may be metabolized in the liver, or it could be accumulated in erythrocytes; however, none are greatly toxic. But if cyanide accumulates in the tissues, it could be attached to tissue cytochrome oxidase, which results in toxic impairment of oxidative phosphorylation. To prevent this side effect, we should care about cyanide accumulation, and for this purpose, infusion of large doses of the drug for long time periods should be prohibited (Moffett and Price 2008; Thomas et al. 2009; Hottinger et al. 2014).
The recommended drug dose for intravenous infusion starts at 0.3–0.5 mcg/kg/min up to a maximum of 10 mcg/kg/min; however, increasing drug dose should be cautiously performed, and effect titration should be the basic monitoring tool for increasing the drug dose to prevent hypotension and toxicity. The best predictor for SNP toxicity is its mean dose which predicts elevated cyanide levels better than any other adverse events of cyanide toxicity, especially in postoperative care of pediatric patients undergoing cardiac surgical procedures (Moffett and Price 2008; Thomas et al. 2009; Moffett et al. 2016).
The onset of action of SNP is within seconds, with its duration to be about 1–2 min and its plasma half-life about 3–4 min (Varon and Marik 2003).
In doses above 3 mcg/kg/min, doses more than 48–72 h, or in patients with renal insufficiency, the risk of drug toxicity increases significantly. There are studies that suggest that in pediatric cardiac surgery, the desired effects of SNP could be gained with 1 mcg/kg/min of the drug and doses above 2 mcg/kg/min should be preferably avoided (Friederich and Butterworth 1995; Hottinger et al. 2014; Drover et al. 2015).
Inhalational forms of SNP have been produced to prevent its toxicity especially in patients with pulmonary hypertension.
Phentolamine Mesylate (Regitine)
Phentolamine mesylate is a nonselective alpha-adrenergic blocker of relatively short duration. Its other less pronounced effects include a direct positive inotropic and chronotropic effects on cardiac muscle and vasodilator effects on vascular smooth muscle. Blocking the presynaptic α2-adrenergic receptors can be the cause of tachycardia and arrhythmias seen with high doses of these drugs.
Phentolamine produces a decrease in systemic vascular resistance that results in an increase in cardiac output. It also reduces pulmonary vascular resistance and pulmonary arterial pressure. The common doses for this drug can be found in Table 4.6. The most important side effects of this drug are significant sinus tachycardia, arrhythmias, and excessive hypotension (Allen et al. 2013).
Table 4.6
A summary of vasoactive drugs including vasodilator and vasoconstrictor drugs used in congenital heart diseases
Drug | Dose | Receptors | Indication | Half-life (duration) | Adverse effects/notes |
|---|---|---|---|---|---|
Vasopressin | 0.01–0.05 U/kg/h | V1, V2 | Refractory hypotension after conventional drugs have failed, heart failure, vasodilatory shock, e.g., septic shock | 10–30 min | Splanchnic ischemia due to its vasoconstrictor action |
Phenylephrine | 0.02–0.3 μg/kg/min | α1 | Hypotension during anesthesia | 5 min | Nausea, vomiting, headache, nervousness |
Nitroglycerin | 0.2–10 μg/kg/min | Vascular myocyte/guanylyl cyclase, cGMP ↑ | Post cardiac surgery for valvular regurgitation; cardiac surgeries where coronaries are involved, e.g., arterial switch operation, Ross operation and repair for anomalous left coronary artery from pulmonary artery, and systemic hypertension | 1–4 min | Hypotension, tachycardia, methemoglobinemia leading to cyanosis, acidosis, convulsions, and coma |
Nitroprusside | 0.2–5 μg/kg/min | Vascular myocyte/guanylyl cyclase, cGMP ↑ | Systemic hypertension, e.g., after repair of coarctation of aorta, malignant hypertension of renal vascular origin, acute and severe valvular regurgitation, low cardiac output state following cardiac surgery, especially after valvular surgery, acute heart failure | 2 min | Excessive hypotension, cyanide toxicity |
Inhaled nitric oxide | 10–40 ppm | Vascular myocyte/cGMP ↑ | Pulmonary hypertension of the newborn | 2–6 s | Nitric oxide should not be used for long term, as it results in methemoglobinemia |
Prostaglandin E1 | 0.01–0.4 μg/kg/min | Vascular myocyte/cAMP ↑ | In newborns who have congenital heart defects (e.g., pulmonary stenosis, tricuspid atresia) and who depend on patent ductus for survival | 0.5–10 min | Hypotension, cardiac arrest, edema |
Fenoldopam | 0.025–0.3 μg/kg/min initial dose, titrate to maximum dose 0.8 μg/kg/min | DA-1, α2 | Severe hypertension | 3–5 min | Hypotension, tachycardia |
Nicardipine | 1–3 μg/kg/min IV infusion, maximum 15 mg/h | Calcium channel antagonist | Severe hypertension | 14.4 h | Headache, hypotension, nausea/vomiting, tachycardia |
Phentolamine mesylate | 1 mg, 0.1 mg/kg, or 3 mg/m2 | α-adrenergic blocking agent, an imidazoline | Hypertension crisis, hypertension in pheochromocytoma, extravasation of catecholamines, pulmonary artery hypertension | 15–30 min | Abdominal pain, nausea, vomiting, diarrhea, exacerbation of peptic ulcer, orthostatic hypotension |
Antihypertensive Agents
Hypertension in pediatric patients may lead to organ damage. Currently, a wide range of antihypertensive agents are available in adult that the majority of them could be used in pediatric patients (Flynn 2011; Chu et al. 2014; Dhull et al. 2016). On the other hand, treatment of neonatal hypertension is a great challenge and needs sophisticated care (Sharma et al. 2014; Sharma et al. 2016).
The current antihypertensive pharmaceutical agents could be categorized mainly in the following subclasses:
Angiotensin-converting enzyme (ACE) inhibitors:
among them, captopril, enalapril, lisinopril, and ramipril are the commonly used agents; however, among other members of the group, fosinopril, perindopril, quinapril, trandolapril, and benazepril could be mentioned. The main ACE inhibitors are summarized in Table 4.7 and nearly all of them are safe for treatment of pediatric hypertension (Chaturvedi et al. 2014a, b; Dhull et al. 2016).
Table 4.7
The main ACE inhibitors in pediatric patients
Drug | Dose | Half-life | Adverse effects |
|---|---|---|---|
Captopril | Oral: 0.3–2.5 mg/kg/day divided every 8–12 h In infants and 0.3–6 mg/kg/day divided every 8–12 h in children and adolescents | Infants: 3.3 h Children: 1–2.3 h | Hypotension Dizziness Headache Rash Hyperkalemia Cough Angioedema |
Enalapril | Oral: 0.1–0.5 mg/kg/day divided every 12 h IV (as enalaprilat): 5–10 μg/kg/dose every 8–24 h | Neonates: 10.3 h Infants and children: 2.7 (1.3–6.3) h Enalaprilat: Neonates: 11.9 (5.9–15.6) h Infants and children: 11.1 (5.1–20.8) h | |
Lisinopril | Oral: initial, 0.07–0.1 mg/kg/dose once daily ≤ 0.5–0.6 mg/kg/day | 11–13 h | |
Ramipril | Oral: 2–6 mg/m2 daily ≤ 10 mg daily | Ramiprilat: 13–17 h |
Angiotensin II receptor antagonists (ARBs):
losartan and valsartan are the prototype drugs in this group; however, other members of the group include: candesartan, eprosartan, irbesartan, olmesartan, and telmisartan. The main ARBs are presented in Table 4.8. Nearly all of ARBs are safe in pediatric patients (Chaturvedi et al. 2014a, b; Dhull et al. 2016).
Table 4.8
The main ARBs used in pediatric patients
Drug | Dose | Half-life | Adverse effects |
|---|---|---|---|
Losartan | Oral: initial, 0.5 mg/kg once daily not to exceed Up to 1.4 mg/kg once daily; should not exceed 150 mg/day | 1.5–2 h Active metabolite: 6–9 h | Hypotension Dizziness Headache Hyperkalemia Hypoglycemia Diarrhea |
Valsartan | 1–5 years: oral dose, 0.4–3.4 mg/kg once daily 6–16 years: initial oral dose, 1.3 mg/kg/dose once daily ≤2.7 mg/kg/dose once daily | 4–5 h |
Calcium channel blockers (CCBs):
they are categorized in two main subgroups including dihydropyridines and non-dihydropyridines; these are safe agents for treatment of pediatric hypertension (Chaturvedi et al. 2014a, b; Dhull et al. 2016). The main CCBs are summarized in Table 4.9.
Table 4.9
The main calcium channel blockers used in pediatric patients
Drug | Dose | Half-life | Adverse effects |
|---|---|---|---|
Amlodipine | Children 6–17 years: 2.5–5 mg once daily or divided every 12 h | 30–50 h | Edema, dizziness, flushing, palpitations, fatigue, nausea, abdominal pain, somnolence |
Nifedipine | Initially, 0.25–0.5 mg/kg daily given in 1 dose or 2 divided doses up to a maximum dosage of 3 mg/kg (up to 120 mg) daily, given in 1 dose or 2 divided doses | 2–7 h | |
Isradipine | Initially, 0.15–0.2 mg/kg daily given in 3–4 divided doses up to a maximum dosage of 0.8 mg/kg (up to 20 mg) daily | Biphasic; initial half-life 1.5–2 h, terminal elimination half-life approximately 8 h |
Diuretics
Diuretic agents are mainly classified in four subgroups which are discussed in Tables 4.10, 4.11, and 4.12 (Dhull et al. 2016; McCammond et al. 2016):
Table 4.10
The main loop diuretics
Drug | Dose | Half-life | Adverse effects |
|---|---|---|---|
Bumetanide | IV, intramuscular, or oral dose: 0.015–0.1 mg/kg/dose every 6–24 h | Neonates: 6 h Infants: 2.4 h | Hyperuricemia Hypomagnesemia Hyponatremia Hypokalemia Metabolic alkalosis |
Ethacrynic acid | Oral: 0.5–1 mg/kg/dose every 6–12 h IV: 1–2 mg/kg/dose every 8–12 h | 2–4 h | |
Furosemide | Oral: 1–2 mg/kg/dose every 6–24 h IV, intramuscular: 0.5–2 mg/kg/dose every 6–24 h Continuous IV infusion: 0.1–0.4 mg/kg/h | 0.5–2 h; 9 h in end-stage renal disease |
Table 4.11
Spironolactone: the main mineralocorticoid (aldosterone) receptor antagonist
Drug | Dose | Half-life | Adverse effects |
|---|---|---|---|
Spironolactone | Oral: initial 1 mg/kg/day in divided doses every 6–24 h ≤ 12.5 to 25 mg/day Maximum: 3.3–6 mg/kg/day divided every 6–24 h; should not exceed 100 mg/day | 1.4 h; active metabolites: 12–20 h | Diarrhea Nausea Vomiting Dizziness Hyperkalemia Gynecomastia |
Table 4.12
Thiazide and thiazide-like diuretics
Drug | Dose | Half-life | Adverse effects |
|---|---|---|---|
Chlorothiazide | Oral: 10–40 mg/kg/day in divided doses every 12 h IV: 4–10 mg/kg/day divided every 12–24 h (maximum 20 mg/kg/day or 500 mg) | 45–120 min | Hyperuricemia Hypomagnesemia Hyponatremia Hypokalemia |
Hydrochlorothiazide | Oral: 1–4 mg/kg/day in divided doses every 12–24 h | 6–15 h | |
Metolazone | Oral: 0.2–0.4 mg/kg/day divided every 12–24 h | 6–20 h |
Loop diuretics (bumetanide, ethacrynic acid, furosemide, torsemide)
Potassium–sparing diuretics (mineralocorticoid “aldosterone” receptor antagonists) which include spironolactone, amiloride, and triamterene
Thiazide diuretics (epitizide, hydrochlorothiazide and chlorothiazide, bendroflumethiazide)
Thiazide–like diuretics (indapamide, chlorthalidone, metolazone)
Adrenergic receptor antagonists (alpha and/or beta blockers):
some of these agents are discussed under the antiarrhythmic categories; however, some other are presented in Table 4.13.
Table 4.13
A number of adrenoceptor blocking agents
Drug | Dose | Half-life | Adverse effects |
|---|---|---|---|
β-blockers | |||
Metoprolol | Initial oral dose: 0.1–0.25 mg/kg/dose twice daily, not to exceed 12.5–25 mg; up to a maximum daily dose of 1–2 mg/kg/dose twice daily, not to exceed 100 mg twice daily | 3–4 h (7–9 h in poor CYP2D6 metabolizers) | Brady-arrhythmias Hypotension Headache Dizziness Fatigue |
Esmolol | IV Children and adolescents 1–17 years of age: 100–500 mcg/kg per minute as constant infusion | 4–7 min | The effects due to β1 selective actions |
Propranolol | 2–4 mg/kg daily in 2 equally divided doses up to 16 mg/kg daily | 3–6 h | |
Mixed alpha + beta blocker | |||
Carvedilol | Initial oral dose: 0.1 mg/kg/day divided twice daily Not to exceed 3.125 mg Up to a maximum daily dose of0.8–1 mg/kg/day; divided twice daily; not to exceed 25 mg twice daily | ||
Labetalol | Oral Initially, 1–3 mg/kg daily given in 2 divided doses. Maximum: 10–12 mg/kg or 1.2 g daily given in 2 divided doses IV injection (severe hypertension) Children 1–17 years of age: 0.2–1 mg/kg up to maximum of 40 mg per dose by direct IV injection. Alternatively, 0.25–3 mg/kg/h by continuous IV infusion | 5.5 h after IV administration and 6–8 h after oral administration | The effects due to intrinsic sympathomimetic action, α1 receptor antagonist |
Peripheral alpha blockers | |||
Prazosin | Initially, 0.05–0.1 mg/kg daily given in 3 divided doses up to 0.5 mg/kg daily in 3 doses | 2–4 h | Dizziness, lightheadedness, headache, drowsiness, lack of energy, weakness, palpitation, nausea |
Terazosin | 1–20 mg once daily | Approximately 12 h | |
Alpha-2 adrenergic agonists | |||
Clonidine | Initially, 0.05–0.1 mg, may repeat up to maximum of 0.8 mg | 6–20 h | Dry mouth Dizziness Drowsiness Sedation Constipation Major depression (for methyldopa) |
Methyldopa | Initial oral dose: 10 mg/kg daily given in 2–4 divided doses Intravenous dose: 20–40 mg/kg per day which should be administrated every 6 h, with max dose of 65 mg/kg or 3 g per day
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