John F. Butterworth, IV
1. Drug errors are a common cause of accidental injury to patients. The author suggests referring to drug package inserts or the Physician Desk Reference to check any unfamiliar drug before it is prescribed or administered.
2. Phenylephrine can be used for hypotension related to low systemic vascular resistance states or as a temporizing therapy for hypovolemia.
3. Epinephrine is a direct α1 and α2 and b1 and b2 agonist not dependent on release of endogenous norepinephrine. In the setting of a dilated left ventricle and myocardial ischemia, epinephrine may increase coronary perfusion pressure and reduce ischemia.
4. Milrinone increases intracellular concentration of cAMP. Milrinone used as a single inotropic agent has favorable effects on myocardial supply/demand balance reducing preload and afterload and has a low tendency to produce tachycardia.
5. Nitroglycerine is a direct vasodilator producing greater venous pooling than arterial dilation. Venous pooling caused by dilation decreases heart size and preload reducing MV02 and usually lessens ongoing ischemia.
NUMEROUS POTENT DRUGS ARE USED to control heart rate (HR) and rhythm, blood pressure (BP), and cardiac output before, during, and after surgery. Patients undergoing cardiovascular and thoracic operations are particularly likely to receive one of these agents. This chapter reviews the indications, mechanisms, dosing, drug interactions, and common adverse events for these drugs. Drug errors are common causes of accidental injury to patients, particularly in hospitalized, critically ill patients. Therefore, we suggest that the package insert or Physicians’ Desk Reference  (which contains the package insert information) be consulted before any unfamiliar drug is prescribed or administered . Fortunately, it has never been easier to obtain drug information. Convenient sources of drug information include numerous books and web sites, some of which are provided at the end of this chapter [2–5]. Using a “smart” mobile telephone or tablet computer, many physicians now maintain a readily updated library of drug information in their hand or pocket at all times.
I. Drug dosage calculations
A. Conversions to milligram or microgram per milliliter
1. Drugs are administered in increments of weight or units. Unfortunately, drugs are not labeled in a uniform manner. Dilution of drugs and calculations are often necessary. Fortunately, most modern infusion pumps do these calculations for the operator, limiting the opportunity for mistakes.
2. A drug labeled z% contains z g/dL; 10 × z equals the number of grams per liter, numerically equivalent to the number of milligrams per milliliter.
a. Example: Mannitol 25% solution contains 25 g/dL, which equals 250 g/L or 250 mg/mL.
b. Example: Lidocaine 2% contains 2 g/dL, or 20 g/L, or 20 mg/mL.
3. Concentrations given as ratios are converted to milligrams or micrograms per milliliter as follows:
1:1,000 = 1 g/1,000 mL = 1 mg/mL
1:1,000,000 = 1 g/1 million mL = 1 μg/mL
a. Example: Epinephrine is packaged for resuscitation in 1:10,000 dilution. Thus, it is one-tenth as concentrated as 1:1,000; therefore, 1:10,000 is 0.1 mg/mL (or 100 μg/mL).
b. Example: A brachial plexus block is to be performed with 0.5% bupivacaine to which epinephrine 1:200,000 must be added. Because the desired concentration is five times greater than 1:1,000,000, 5 μg of epinephrine should be added for each milliliter of bupivacaine.
B. Calculating infusion rates using standard drip concentrations (adults)
1. Step 1. Dose rate (μg/min): Calculate the desired per-minute dose. Example: A 70 kg patient who is to receive dopamine at 5 μg/kg/min needs a 350 μg/min dose rate.
2. Step 2. Concentration (μg/mL): Calculate how many micrograms of drug are in each milliliter of solution. To calculate concentration (μg/mL), simply multiply the number of milligrams in 250 mL by 4. Example: When nitroglycerin is diluted 100 mg/250 mL, there are 100 × 4 = 400 μg/mL. Example: Dopamine, 200 mg, added to 250 mL fluid = 200/250 mg/mL = 800 mg/L = 800 μg/mL concentration.
3. Step 3. Volume infusion rate (mL/min): Divide the dose rate by the concentration (μg/min ÷ μg/mL = mL/min). The infusion pump should be set for this volume infusion rate. Example: 350 μg/min ÷800 μg/mL = 0.44 mL/min. Conversion of volume rate from milliliters per minute to milliliters per hour simply involves multiplying by 60 min/h (0.44 mL/min × 60 = 26 mL/h).
4. Table 2.1 can be consulted as an alternative means for determining vasoactive drug infusion rates for patients of different weights.
5. Finally, and perhaps most importantly, the wide availability of micropressor-controlled, programmable infusion pumps has largely eliminated the need for complex calculations at the bedside.
C. Preparation of drug infusions for pediatric patients
1. Most pediatric anesthesia departments, critical care units, and pharmacies have specific preferences as to how drugs should be mixed prior to infusion. We strongly recommend that practitioners adhere to the predominant practice in their unit, whether or not the practitioner may perceive it to be optimal. In general, patient safety is maximized when variation is minimized. We discuss two of the more common ways in which drugs are diluted for pediatric patients in the succeeding sections.
2. Technique A: Standard, single drug concentration for all patients
a. Advantages are that it is simple (no arithmetic calculations are required) and the fluid volume administered scales upward appropriately with weight.
b. Disadvantages are that the standard dilution for each drug must be remembered, and volume infusion rates may be excessive in critically ill infants.
3. Technique B: Custom drug dilution based on patient weight. This method permits infusion of a single fluid volume rate to patients of any weight. Our opinion is that this technique maximizes the possibility for drug dilution mistakes.
Table 2.1 Vasoactive drug infusion rates
a. Step 1. Decide on a starting dose per kilogram for the drug. Some standard values are as follows:
b. Step 2. Multiply starting dose (in μg/kg/min) by weight (in kg) to give starting dose rate in μg/min.
c. Step 3. Decide on volume rate of fluid that should carry this starting dose of drug into the patient:
These volumes may be decreased substantially if a continuous carrier infusion is utilized.
d. Step 4. Divide starting dose rate (step 2) by volume rate (step 3) to give desired concentration of drug. Units cancel: (μg/min)/(mL/min) = μg/mL.
Example: In a 6.3 kg baby
(1) Select standard starting dosages of dopamine and isoproterenol.
(2) Calculate starting dose rate:
(a) Dopamine: 5 μg/kg/min × 6 kg = 30 μg/min.
(b) Isoproterenol: 0.1 μg/kg/min × 6 kg = 0.6 μg/min.
(3) Choose volume rate: 0.05 mL/min.
(4) Calculate concentration:
(a) Dopamine: 30 μg/min ÷ 0.05 mL/min = 600 μg/mL.
(b) Isoproterenol: 0.6 μg/min ÷ 0.05 mL/min = 12 μg/mL.
(5) Dilute drugs:
(a) Dopamine: 600 mg/L (or 150 mg/250 mL).
(b) Isoproterenol: 12 mg/L (or 3 mg/250 mL).
D. Pediatric resuscitation doses. We find it convenient to prepare syringes of certain drugs (e.g., epinephrine and atropine) so that they contain a standard emergency dose for the patient.
II. Drug receptor interactions
A. Receptor activation. Can responses to a given drug dose be predicted? The short answer is: Partially. The more accurate answer is: Not with complete certainty. Many factors determine the magnitude of response produced by a given drug at a given dose.
1. Pharmacokinetics relates the dose to the concentrations that are achieved in plasma or at the effect site. In brief, these concentrations are affected by the drug’s volume of distribution and clearance, and for drugs administered orally, by the fractional absorption [6,7].
2. Pharmacodynamics relates drug concentrations in plasma or at the effect site to the drug effect.
a. Concentration of drug at the effect site (receptor) is influenced by the concentration of drug in plasma, tissue perfusion, lipid solubility, and protein binding; diffusion characteristics, including state of ionization (electrical charge); and local metabolism.
b. Number of receptors per gram of end-organ tissue varies.
(1) Upregulation (increased density of receptors) is seen with a chronic decrease in receptor stimulation. Example: Chronic administration of β-adrenergic receptor antagonists increases the number of β-adrenergic receptors.
(2) Downregulation (decreased density of receptors) is caused by a chronic increase in receptor stimulation. Example: Chronic treatment of asthma with β-adrenergic receptor agonists reduces the number of β-adrenergic receptors.
c. Drug receptor affinity and efficacy may vary.
(1) Receptor binding and activation by an agonist produces a biochemical change in the cell. Example: α-Adrenergic receptor agonists increase protein kinase C concentrations within smooth-muscle cells. β-Adrenergic receptor agonists increase intracellular concentrations of cAMP.
(2) The biochemical change may produce a cellular response. Example: Increased intracellular protein kinase C produces an increase in intracellular [Ca2+], which results in smooth-muscle contraction. Conversely, increased intracellular concentrations of cAMP relax vascular smooth muscle but increase the inotropic state of cardiac muscle.
(3) The maximal effect of a partial agonist is less than the maximal effect of a full agonist.
(4) Receptor desensitization may occur when prolonged agonist exposure to receptor leads to loss of cellular responses with agonist–receptor binding. An example of this is the reduced response to β1-adrenergic receptor agonists that occurs in patients with chronic heart failure (CHF), as a result of the increased intracellular concentrations of β-adrenergic receptor kinase, an enzyme which uncouples the receptor from its effector enzyme adenylyl cyclase.
(5) Other factors including acidosis, hypoxia, and drug interactions can reduce cellular response to receptor activation.
III. Pharmacogenetics and genomics
In the future, pharmacogenetics, or how drug actions or toxicities are influenced by an individual’s genetic make-up, may become a tool in helping anesthesiologists select among therapeutic options. We are learning, for example, that the genetic profile of the individual may impact the degree to which patients respond to adrenergic therapies, including vasopressors. Life-threatening arrhythmias, such as Long QT syndrome, may result from therapy with a number of commonly prescribed agents, and relatively common genetic sequence variations are now known to be an underlying predisposing factor. Droperidol, which is highly effective and safe at small doses for preventing or treating postoperative nausea, has been shown (at larger doses) to cause QT-interval lengthening and increase risk of Torsades de Pointes in a small cohort of susceptible patients. Therefore, a larger number of patients will be deprived of this useful medication because of our inability to identify the small number of patients who have the genetic markers associated with this rare but disastrous complication. Industry and academia are rapidly progressing toward simple assay-based genetic screens capable of identifying patients with these and other risks for adverse or inadequate drug responses, including heparin or warfarin resistance. Unfortunately, at the present time, commercially available screens are rare and have not been sufficiently evaluated to be considered the standard care. As such, detailed family history is the only practical means through which we can identify such genetic risks. At the same time, genetic variations may occur spontaneously or be present in a family but not be manifested with symptoms (phenotypically silent). Hence, continuous monitoring for adverse or highly variable drug responses, particularly those related to arrhythmias or BP instability, is the cornerstone of cardiovascular management in the perioperative period.
IV. Guidelines for prevention and treatment of cardiovascular disease
Drug treatment and drug prevention for several common cardiovascular diseases have been described in clinical practice guidelines published by national and international organizations. We provide references for the convenience of our readers. Because these recommendations evolve from year to year, we strongly recommend that readers check whether these guidelines may have been updated since publication of this volume.
1. Primary prevention (see Ref. 7)
2. Established disease (see Refs. 8,9)
3. Preoperative cardiac evaluation and prophylaxis during major surgery (see Refs. 10,11)
B. CHF (see Refs. 12,13)
C. Hypertension (see Refs. 14,15)
D. Atrial fibrillation prophylaxis (see Ref. 11)
Figure 2.1 Schematic representation of the adrenergic receptors present on the sympathetic nerve terminal and vascular smooth-muscle cell. NE is released by electrical depolarization of the nerve terminal; however, the quantity of NE release is increased by neuronal (presynaptic) β2-receptor or muscarinic-cholinergic stimulation and is decreased by activation of presynaptic α2-receptors. On the postsynaptic membrane, stimulation of α1- or α2-adrenergic receptors causes vasoconstriction, whereas β2-receptor activation causes vasodilation. Prazosin is a selective α1-antagonist drug. Note that NE at clinical concentrations does not stimulate β2-receptors, but epinephrine (E) does. (From Opie LH. The Heart: Physiology from the Cell to the Circulation. Philadelphia, PA: Lippincott Williams & Wilkins; 1998:17–41, with permission.)
A. a-Adrenergic receptor pharmacology (Fig. 2.1)
1. Postsynaptic α-adrenergic receptors mediate peripheral vasoconstriction (both arterial and venous), especially with neurally released norepinephrine (NE). Selective activation of cardiac α-adrenergic receptors increases inotropy while decreasing the HR. (Positive inotropy from α-adrenergic agonists can only be demonstrated in vitro or by selective drug administration in coronary arteries to avoid peripheral effects that normally overwhelm the cardiac actions.)
2. α-Adrenergic receptors on presynaptic nerve terminals decrease NE release through negative feedback. Activation of brain α-adrenergic receptors (e.g., with clonidine) lowers BP by decreasing sympathetic nervous system activity and causes sedation (e.g., with dexmedetomidine). Postsynaptic α2-adrenergic receptors mediate constriction of vascular smooth muscle.
3. Drug interactions
a. Reserpine interactions. Reserpine depletes intraneuronal NE and chronic use induces a “denervation hypersensitivity” state. Indirect-acting sympathomimetic drugs show diminished effect because of depleted NE stores, whereas direct-acting or mixed-action drugs may produce exaggerated responses because of receptor upregulation. This is of greater laboratory than clinical interest because of the rarity with which reserpine is now prescribed to patients. For the rare patient receiving reserpine, we recommend titrated dosages of direct-acting drugs and careful monitoring of BP.
b. Tricyclic (and tetracyclic) antidepressant or cocaine interactions. These drugs block the reuptake of catecholamines by prejunctional neurons and increase the catecholamine concentration at receptors. Interactions between these drugs and sympathomimetic agents can be very severe and of comparable or greater danger than the widely feared monoamine oxidase (MAO) inhibitor reactions. In general, if sympathomimetic drugs are required, small dosages of direct-acting agents represent the best choice.
4. Specific agents
a. Selective agonists
(1) Methoxamine (Vasoxyl)
(a) Methoxamine is a synthetic drug and is not a catecholamine. It is of mostly historic interest.
(b) Actions. The drug is a selective, direct, α1 agonist that produces vasoconstriction.
(c) Offset. A longer duration of action (1 to 1.5 h intramuscularly [IM]) than phenylephrine or NE; not metabolized by either MAO or catechol-O-methyl transferase (COMT).
(d) Indications for use—similar to phenylephrine
(e) Clinical use
(i) Methoxamine dose (adult): 1 to 5 mg intravenous (IV) bolus; 10 to 20 mg IM.
(ii) The long duration of action of methoxamine makes it more difficult to titrate the dosage to rapidly changing hemodynamic conditions than with phenylephrine, vasopressin, or NE.
(2) Phenylephrine (Neo-Synephrine) 
(a) Phenylephrine is a synthetic noncatecholamine.
(b) Actions. The drug is a selective α1-adrenergic agonist with minimal β-adrenergic effects. It causes vasoconstriction, primarily in arterioles.
(c) Offset occurs by redistribution and rapid metabolism by MAO; there is no COMT metabolism.
(d) Advantages. A direct agonist with short duration (less than 5 min), it increases perfusion pressure for the brain, kidney, and heart in the presence of low SVR states. When used during hypotension, phenylephrine will increase coronary perfusion pressure without altering myocardial contractility. If hypertension is avoided, myocardial oxygen consumption (MVO2) does not increase substantially. If contractility is depressed because of ischemia, phenylephrine will sometimes produce an increased CO from an increase in coronary perfusion pressure. It is useful for correcting hypotension in patients with CAD, hypertrophic subaortic stenosis, tetralogy of Fallot, or valvular aortic stenosis.
(e) Disadvantages. It may decrease stroke volume (SV) and CO secondary to increased afterload; it may increase pulmonary vascular resistance (PVR); it may decrease renal, mesenteric, and extremity perfusion. Reflex bradycardia, usually not severe, may occur but will usually respond to atropine. Phenylephrine rarely may be associated with coronary artery spasm or spasm of an internal mammary, radial, or gastroepiploic artery bypass graft.
(f) Indications for use
(i) Hypotension due to peripheral vasodilation, low SVR states (e.g., septic shock, or to counteract effects of nitroglycerine)
(ii) For patients with supraventricular tachycardia (SVT), reflex vagal stimulation in response to increased BP may terminate the arrhythmia; phenylephrine treats both the hypotension and the arrhythmia.
(iii) It can oppose right-to-left shunting during acute cyanotic spells in tetralogy of Fallot.
(iv) Temporary therapy of hypovolemia until blood volume is restored, although a drug with positive inotropic action (e.g., ephedrine) usually is a better choice in patients without CAD (or hypertrophic obstructive cardiomyopathy), and in general, vasoconstrictors should not be viewed as effective treatments for hypovolemia.
(g) Administration. IV infusion (central line preferable) or IV bolus
(h) Clinical use
(i) Phenylephrine dose
(a) IV infusion: 0.5 to 10 μg/kg/min.
(b) IV bolus: 1 to 10 μg/kg, increased as needed (some patients with peripheral vascular collapse may require larger bolus injections to raise SVR).
(c) For tetralogy of Fallot spells in children: 5 to 50 μg/kg IV as a bolus dose.
(a) IV infusion: Often mix 10 or 15 mg in 250 mL IV fluid (40 or 60 μg/mL).
(b) IV bolus: Dilute to 40 to 100 μg/mL.
(iii) Nitroglycerin may be administered while maintaining or increasing arterial BP with phenylephrine. This combination may serve to increase myocardial oxygen supply while minimizing increases in MVO2.
(iv) Phenylephrine is the vasopressor of choice for short-term correction of excessive vasodilation in most patients with CAD or aortic stenosis.
b. Mixed agonists
(1) Dopamine (Intropin) 
See subsequent Section VI: Positive inotropic drugs.
(a) Ephedrine is a plant-derived alkaloid with sympathomimetic effects.
(i) Mild direct α-, β1-, and β2-adrenergic agonist
(ii) Indirect NE release from neurons
(c) Offset. 5 to 10 min IV; no metabolism by MAO or COMT; renal elimination
(i) Easily titrated pressor and inotrope that rarely produces unexpected excessive responses
(ii) Short duration of action with IV administration (3 to 10 min); lasts up to 1 h with IM administration
(iii) Limited tendency to produce tachycardia
(iv) Does not reduce blood flow to placenta; safe in pregnancy
(v) Good agent to correct sympathectomy-induced relative hypovolemia and decreased SVR after spinal or epidural anesthesia
(i) Efficacy is reduced when NE stores are depleted.
(ii) Risk of malignant hypertension with MAO inhibitors or cocaine
(iii) Tachyphylaxis with repeated doses (thus rarely administered by continuous infusion)
(i) Hypotension due to low SVR or low CO, especially if HR is low, and particularly with spinal or epidural anesthesia
(ii) Temporary therapy of hypovolemia until circulating blood volume is restored, although, as previously noted, in general vasoconstrictors should not substitute for definitive treatment of hypovolemia
(g) Administration. IV, IM, subcutaneous (SC), by mouth (PO)
(h) Clinical use
(i) Ephedrine dose: 5 to 10 mg IV bolus, repeated or increased as needed; 25 to 50 mg IM.
(ii) Ephedrine is conveniently mixed in a syringe (5 to 10 mg/mL) and can be given as an IV bolus into a freely running IV line.
(iii) Ephedrine is a useful, quick-acting, titratable IV pressor that can be administered via a peripheral vein during anesthesia.
(3) Epinephrine (Adrenaline)
See subsequent Section IV: Positive inotropic drugs.
(4) NE (noradrenaline, Levophed) 
(a) NE is the primary physiologic postganglionic sympathetic neurotransmitter; NE also is released by adrenal medulla and central nervous system (CNS) neurons.
(i) Direct α1- and α2-adrenergic actions and β1-adrenergic agonist action
(ii) Limited β2-adrenergic effect in vivo, despite NE being a more powerful β2-adrenergic agonist than dobutamine in vitro
(c) Offset is by redistribution, neural uptake, and metabolism by MAO and COMT.
(i) Direct adrenergic agonist. Equipotent to epinephrine at β1-adrenergic receptors
(ii) Redistributes blood flow to brain and heart because all other vascular beds are constricted.
(iii) Elicits intense α1- and α2-adrenergic agonism; may be effective as vasoconstrictor when phenylephrine (α1 only) lacks efficacy
(i) Reduced organ perfusion: Risk of ischemia of kidney, skin, liver, bowel, and extremities
(ii) Myocardial ischemia possible; increased afterload, HR. Contractility may increase, be unchanged, or even decrease. Coronary spasm may be precipitated.
(iii) Pulmonary vasoconstriction
(v) Risk of skin necrosis with SC extravasation
(f) Indications for use
(i) Peripheral vascular collapse when it is necessary to increase SVR (e.g., septic shock or “vasoplegia” after cardiopulmonary bypass [CPB])
(ii) Conditions in which increased SVR is desired together with cardiac stimulation
(iii) Need for increased SVR in which phenylephrine has proved ineffective
(g) Administration. IV only, by central line only
(h) Clinical use
(i) Usual NE starting infusion doses: 15 to 30 ng/kg/min IV (adult); usual range, 30 to 300 ng/kg/min.
(ii) Minimize duration of use; monitor patient for oliguria and metabolic acidosis.
(iii) NE can be used with vasodilator (e.g., nitroprusside or phentolamine) to counteract α stimulation while leaving β1-adrenergic stimulation intact; however, if intense vasoconstriction is not required, we recommend that a different drug be used.
(iv) For treating severe right ventricular (RV) failure associated with cardiac surgery, the simultaneous infusion of NE into the left atrium (through a left atrial catheter placed intraoperatively) plus inhaled NO and/or nitroglycerine by IV infusion is useful. The left atrial NE reaches the systemic vascular bed first and it is largely metabolized peripherally before it reaches the lung where it might increase PVR (had the NE been infused through a venous line) (Table 2.2).
(5) Interactions with MAO inhibitors
(a) MAO is an enzyme that deaminates NE, dopamine, and serotonin. Thus, the MAO inhibitors treat severe depression by increasing catecholamine concentrations in the brain by inhibiting catecholamine breakdown. Administration of indirectly acting adrenergic agonists or meperidine to patients taking MAO inhibitors can produce a life-threatening hypertensive crisis. Ideally, 2 to 3 wks should elapse between discontinuing the hydrazine MAO inhibitor phenelzine and elective surgery. Nonhydrazine MAO inhibitors (isocarboxazid, tranylcypromine) require 3 to 10 days for offset of effect. Selegiline at doses 10 mg or less per day should present fewer adverse drug interactions than other MAO inhibitors.
(b) The greatest risk of inducing a hyperadrenergic state occurs with indirect- acting sympathomimetic drugs (such as ephedrine), because such agents release the intraneuronal stores of NE that were increased by the MAO inhibitor. Because dopamine releases NE, it should be initiated with caution in the MAO-inhibited patient.
Table 2.2 Acute treatment of pulmonary hypertension and RV failure
(c) In MAO-inhibited patients, preferred drugs are those with purely direct activity: epinephrine, NE, isoproterenol, phenylephrine, vasopressin, and dobutamine. All pressor drugs should be used cautiously, in small dosages with BP monitoring and observation of the electrocardiogram (ECG) for arrhythmias.
B. Vasopressin pharmacology and agonists 
a. Vasopressin is an endogenous antidiuretic hormone that in high concentrations produces a direct peripheral vasoconstriction through activation of smooth-muscle V1 receptors. Vasopressin has no actions on β-adrenergic receptors, so it may produce less tachycardia than epinephrine when used for resuscitation after cardiac arrest. Vasopressin has been administered intra-arterially in a selective fashion to control gastrointestinal bleeding.
b. Vasopressin produces relatively more vasoconstriction of skin, skeletal muscle, intestine, and adipose tissue than of coronary or renal beds. Vasopressin causes cerebrovascular dilation.
a. Vasopressin is a very potent agent which acts independently of adrenergic receptors.
b. Some studies suggest that vasopressin may be effective at maintaining adequate SVR in severe acidosis, sepsis, or after CPB, even when agents such as phenylephrine or NE have proven ineffective.
c. Vasopressin may restore coronary perfusion pressure after cardiac arrest without also producing tachycardia and arrhythmias, as is common when epinephrine is used for this purpose.
a. Vasopressin produces a variety of unpleasant signs and symptoms in awake patients, including pallor of skin, nausea, abdominal cramping, bronchoconstriction, and uterine contractions.
b. Decreases in splanchnic blood flow may be of concern in patients receiving vasopressin for more than a few hours, particularly when vasopressin is coadministered with agents such as α-adrenergic agonists and positive inotropic drugs. Increases in serum concentrations of bilirubin and of “liver” enzymes are common.
c. Vasopressin may be associated with a decrease in platelet concentration.
d. Lactic acidosis is common in patients receiving vasopressin infusion (but these patients are generally critically ill and already receiving other vasoactive agents).
4. Clinical use
a. Vasopressin has been used as an alternative to epinephrine in treating countershock-refractory ventricular fibrillation (VF) in adults. The 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science suggest that vasopressin may be substituted either for the first or second dose of epinephrine during resuscitation, but that there is no convincing evidence that inclusion of vasopressin in resuscitation will improve outcomes relative to outcomes obtained with epinephrine alone. The typical vasopressin resuscitation dose is 40 units as an IV bolus.
b. Vasopressin has been used in a variety of conditions associated with vasodilatory shock, including sepsis, the “vasoplegic” syndrome after CPB, and for hypotension occurring in patients receiving ACE inhibitors (or angtiotensin receptor blockers) and general anesthesia. Typical adult doses range from 4 to 6 units/h. We have found this drug to be effective and useful, but sometimes associated with troublesome metabolic acidosis. We speculate that the latter may be the result of inadequate visceral perfusion.
VI. Positive inotropic drugs
A. Treatment of low CO 
1. Goals. Increase organ perfusion and oxygen delivery to tissues
a. Increase CO by increasing SV, HR (when appropriate) or both
b. Maximize myocardial oxygen supply (increase diastolic arterial pressure, diastolic perfusion time, and blood O2 content; decrease left ventricular end-diastolic pressure [LVEDP])
c. Provide an adequate mean arterial pressure (MAP) for perfusion of other organs
d. Minimize increases in myocardial oxygen demand by avoiding tachycardia and left ventricular (LV) dilation
e. Metabolic disturbances, arrhythmias, or cardiac ischemia, if present, should be treated concurrently.
f. Drug treatment of critically ill patients with intrinsic myocardial failure may include the following cardiac stimulants:
(1) β1-Adrenergic stimulation
(2) Phosphodiesterase (PDE) inhibition
(3) Dopaminergic stimulants
(4) Calcium sensitizers (increase calcium sensitivity of contractile proteins)
2. Monitoring. Positive inotropic drug dosing is most effectively regulated using data from the arterial line, a monitor of cardiac output, and/or echocardiography. In addition, monitoring of mixed venous oxygen saturation can be extremely valuable. The inotropic drug dosage can be titrated to CO and BP endpoints, together with assessment of organ perfusion, e.g., urine output and concentration.
B. cAMP-dependent agents
1. b-Adrenergic and dopaminergic receptor agonists
a. Similarities among sympathomimetic drugs
(1) β1-agonist effects are primarily stimulatory.
(2) β2 agonists cause vasodilation and bronchodilation, and they also increase HR and contractility (albeit with less potency than β1 agonists).
(3) Postsynaptic dopaminergic receptors mediate renal and mesenteric vasodilation, increase renal salt excretion, and reduce gastrointestinal motility. Presynaptic dopaminergic receptors inhibit NE release.
(4) Diastolic ventricular dysfunction. Cardiac β-receptor activation enhances diastolic ventricular relaxation by facilitating the active, energy-consuming process that pumps free intracellular Ca2+into storage sites. Abnormal relaxation occurring in ischemia and other myocardial disorders leads to increased diastolic stiffness. By augmenting diastolic relaxation, β-adrenergic receptor agonists reduce LVEDP and heart size (LV end-diastolic volume [LVEDV]), improve diastolic filling, reduce left atrial pressure (LAP), and improve the myocardial oxygen supply–demand ratio.
(5) Systolic ventricular dysfunction. More complete ventricular ejection during systole will reduce the LV end-systolic volume. This reduces heart size, LV systolic wall tension (by Laplace’s law), and myocardial oxygen consumption (MVO2).
(6) Myocardial ischemia. The net effects of β-receptor stimulation on myocardial O2 supply and demand are multifactorial and may be difficult to predict. MVO2 tends to increase as HR and contractility rise, but MVO2 is reduced by lowering LVEDV. β Agonists improve O2 supply when LVEDP is decreased, but can worsen the supply–demand ratio particularly if HR rises or diastolic BP is lowered.
(7) Hypovolemia is deleterious to the patient with heart failure just as it is for the patient with normal ventricular function; however, volume overload may lead to myocardial ischemia by restricting subendocardial perfusion.
(8) There is a risk of tissue damage or sloughing when vasoactive drugs extravasate outside of a vein. In general, catecholamine vasoconstrictors should not be infused for long periods of time through a peripheral IV line because of the risk of extravasation or infiltration. These drugs may be given through peripheral IV lines provided that
(a) No central venous catheter is available.
(b) The drug is injected only into a free-flowing IV line.
(c) The IV site is observed during and after the injection for signs of infiltration or extravasation.
b. Dobutamine (Dobutrex) 
(1) Dobutamine is a synthetic catecholamine formulated as a racemic mixture.
(a) Direct β1 agonist, with limited β2 and α1 effects. Dobutamine has no α2 or dopaminergic activity.
(b) Dobutamine increases cardiac inotropy principally via its β1 (and perhaps also by α1) agonism, but HR is increased only by the β1 effect.
(c) On blood vessels, dobutamine is predominantly a vasodilator drug. Mechanisms for vasodilation include the following:
(i) β2-mediated vasodilation that is only partially counteracted by (−) dobutamine’s α1 constrictor effects
(ii) The (+) dobutamine enantiomer and its metabolite, (+)-3-O-methyldobutamine, are α1 antagonists. Thus, as dobutamine is metabolized, any α1 agonist actions of the drug should diminish over time.
(3) Offset. Offset of action is achieved by redistribution, metabolism by COMT, and conjugation by glucuronide in liver; an active metabolite is generated. Plasma half-life is 2 min.
(a) At low doses there is generally less tachycardia than with “equivalently inotropic” doses of isoproterenol or dopamine, whereas some studies show that “equivalently inotropic” doses of epinephrine produce LESS tachycardia than dobutamine.
(b) Afterload reduction (SVR and PVR) may improve LV and RV systolic function, which can benefit the heart with right and/or LV failure.
(c) Renal blood flow may increase (due to a β2 effect), but not as much as with comparable (but low) doses of dopamine or dopexamine.
(a) Tachycardia and arrhythmias are dose-related and can be severe.
(b) Hypotension may occur if the reduction in SVR is not fully offset by an increase in CO; dobutamine is an inotrope but is not a pressor.
(c) Coronary steal is possible.
(d) The drug is a nonselective vasodilator: Blood flow may be shunted from kidney and splanchnic bed to skeletal muscle.
(e) Tachyphylaxis has been reported when infused for more than 72 h.
(f) Mild hypokalemia may occur.
(g) As a partial agonist, dobutamine can inhibit actions of full agonists (e.g., epinephrine) under certain circumstances.
(6) Indications. Low CO states, especially with increased SVR or PVR
(7) Administration. IV only (central line is preferable, but dobutamine has little vasoconstrictor activity, minimizing risk of extravasation).
(8) Clinical use
(a) Dobutamine dose: IV infusion, 2 to 20 μg/kg/min. Some patients may respond to initial doses as low as 0.5 μg/kg/min and, at such low doses, HR usually does not increase.
(b) Dobutamine increases MVO2 to a lesser degree than CO. Dobutamine increases coronary blood flow to a greater degree than dopamine when either agent is given as a single drug. However, addition of nitroglycerin to dopamine may be equally effective.
(c) Dobutamine acts similar to a fixed-ratio combination of an inotropic drug and a vasodilator drug. These two components cannot be titrated separately.
(d) In patients undergoing coronary surgery, dobutamine produces more tachycardia than epinephrine when administered to produce the same increase in SV .
(e) When dobutamine is given to β-blocked patients, SVR may increase.
(f) Routine administration of dobutamine (or any other positive inotrope) is not recommended. 
c. Dopamine (Intropin) 
(1) Dopamine is a catecholamine precursor to NE and epinephrine found in nerve terminals and the adrenal medulla.
(a) Direct action: α1-, β1-, β2-adrenergic, and dopaminergic (DA1) agonist
(b) Indirect action: Induces release of stored neuronal NE
(c) The dose versus response relationship is often described as if “carved in stone”; however, the relationship between dose and concentration and between dose and response is highly variable from patient to patient.
(3) Offset is achieved by redistribution, uptake by nerve terminals plus metabolism by MAO and COMT.
(a) Increased renal perfusion and urine output at low to moderate dosages (partially due to a specific DA1 agonist effect)
(b) Blood flow shifts from skeletal muscle to kidney and splanchnic beds.
(c) BP response is easy to titrate because of its mixed inotropic and vasoconstrictor properties.
(a) There is a significant indirect-acting component; response can diminish when neuronal NE is depleted (e.g., in patients with CHF).
(b) Sinus, atrial, or ventricular tachycardia (VT) and arrhythmias may occur.
(c) Maximal inotropic effect less than that of epinephrine.
(d) Skin necrosis may result from extravasation.
(e) Renal vasodilating effects are over-ridden by α-mediated vasoconstriction at dosages greater than 10 μg/kg/min with risk of renal, splanchnic, and skin necrosis. Urine output should be monitored.
(f) Pulmonary vasoconstriction is possible.
(g) MVO2 increases, and myocardial ischemia may occur if coronary flow does not increase commensurately.
(h) In some patients with severe HF, the increased BP at increased doses may be detrimental. Such patients benefit from adding a vasodilator.
(a) Hypotension due to low CO or low SVR (although other agents are superior for the latter indication)
(b) Temporary therapy of hypovolemia until circulating blood volume is restored (but vasoconstrictors should not substitute or delay primary treatment of hypovolemia)
(c) “Recruiting renal blood flow” for renal failure or insufficiency (widely used for this purpose, but limited evidence basis)
(7) Administration: IV only (preferably by central venous line)
(8) Clinical use
(a) Dopamine dose: 1 to 20 μg/kg/min IV.
(b) Often mix 200 mg in 250 mL IV solution (800 μg/mL).
(c) Good first choice for temporary treatment of hypotension until intravascular volume can be expanded or until a specific diagnosis can be made.
(d) Correct hypovolemia if possible before use (as with all pressors)
(e) After cardiac surgery if inotropic response is not adequate at dopamine doses of 5 to 10 μg/kg/min, we recommend a switch to a more powerful agonist such as epinephrine, or a switch to or addition of milrinone.
(f) Consider adding a vasodilator (e.g., nitroprusside) when BP is adequate and afterload reduction would be beneficial (or better still, reduce the dose of dopamine).
d. Dopexamine 
(a) Dopexamine is a synthetic analog of dobutamine with vasodilator action. Its cardiac inotropic and chronotropic activity is caused by direct β2-agonist effects and by NE actions (due to baroreceptor reflex activation and neuronal uptake-1 inhibition) that indirectly activate β1-receptors. In CHF, there is selective β1 downregulation, with relative preservation of β2-receptor number and coupling. The latter assume greater than normal physiologic importance, making dopexamine of theoretically greater utility than agents with primary β1-receptor activity. Although dopexamine has been used in Europe for roughly a decade, the drug will likely never be available in the United States.
(b) Receptor activity
α1 and α2: Minimal
β1: Little direct effect, some indirect; β2: Direct agonist
DA1: Potent agonist (activation increases renal blood flow)
(c) Inhibits neuronal catecholamine uptake-1, increasing NE actions
(d) Hemodynamic actions
(2) Offset. Half-life: 6 to 11 min. Clearance is by uptake into tissues (catecholamine uptake mechanisms) and by hepatic metabolism.
(a) Lack of vasoconstrictor activity avoids α-mediated complications.
(b) Decreased renovascular resistance might theoretically help preserve renal function after ischemic insults.
(a) Less effective positive inotrope than other agents (e.g., epinephrine, milrinone)
(b) Dose-dependent tachycardia may limit therapy.
(d) Not approved by the U.S. Food and Drug administration for release in the United States.
(5) Indications. Treatment of low CO states
(6) Administration. IV
(7) Clinical use
(a) Dopexamine dose: 0.5 to 4 μg/kg/min IV (maximum 6 μg/kg/min).
(b) Hemodynamic and renal effects similar to the combination of variable doses of dobutamine with dopamine 1 μg/kg/min (renal dose) or fenoldopam 0.05 μg/kg/min.
e. Epinephrine (Adrenaline) 
(1) Epinephrine is a catecholamine produced by the adrenal medulla.
(a) Direct agonist at α1-, α2-, β1-, and β2-receptors
(b) Dose response (adult, approximate)
(c) Increased contractility with all dosages, but SVR may decrease, remain unchanged, or increase dramatically depending on the dosage. CO usually increased but, at extreme resuscitation dosages, α-receptor–mediated vasoconstriction may cause a lowered SV due to high afterload.
(3) Offset occurs by uptake by neurons and tissue and by metabolism by MAO and COMT (rapid).
(a) This drug is direct-acting; its effects are not dependent on release of endogenous NE.
(b) Potent α- and β-adrenergic stimulation results in greater maximal effects and produce equivalent increases in SV with tachycardia after heart surgery than dopamine or dobutamine.
(c) It is a powerful inotrope with variable (and dose-dependent) α-adrenergic effect. Lusitropic effect (β1) enhances the rate of ventricular relaxation.
(d) BP increases may blunt tachycardia due to reflex vagal stimulation.
(e) It is an effective bronchodilator and mast cell stabilizer, useful for primary therapy of severe bronchospasm, anaphylactoid, or anaphylactic reactions.
(f) With a dilated LV and myocardial ischemia, epinephrine may increase diastolic BP and decrease heart size, reducing myocardial ischemia. However, as with any inotropic drug, epinephrine may induce or worsen myocardial ischemia.
(a) Tachycardia and arrhythmias at higher doses.
(b) Organ ischemia, especially kidney, secondary to vasoconstriction, may result. Renal function must be closely monitored.
(c) Pulmonary vasoconstriction may occur, which can produce pulmonary hypertension and possibly RV failure; addition of a vasodilator may counteract this.
(d) Epinephrine may produce myocardial ischemia. Positive inotropy and tachycardia increase myocardial oxygen demand and reduce oxygen supply.
(e) Extravasation from a peripheral IV cannula can cause necrosis; thus, administration via a central venous line is preferable.
(f) As with most adrenergic agonists, increases of plasma glucose and lactate occur. This may be accentuated in diabetics.
(g) Initial increases in plasma K+ occur due to hepatic release, followed by decreased K+ due to skeletal muscle uptake.
(a) Cardiac arrest (especially asystole or VF); electromechanical dissociation. Epinephrine’s efficacy is believed to result from increased coronary perfusion pressure during cardiopulmonary resuscitation (CPR). Recently, the utility of high-dose (0.2 mg/kg) epinephrine was debated, the consensus is that there is no outcome benefit to “high-dose” epinephrine.
(b) Anaphylaxis and other systemic allergic reactions; epinephrine is the agent of choice.
(c) Cardiogenic shock, especially if a vasodilator is added
(e) Reduced CO after CPB
(f) Hypotension with spinal or epidural anesthesia can be treated with low-dose (1 to 4 μg/min) epinephrine infusions as conveniently and effectively as with ephedrine boluses .
(7) Administration. IV (preferably by central line); via endotracheal tube (rapidly absorbed by tracheal mucosa); SC
(8) Clinical use
(a) Epinephrine dose
(i) SC: 10 μg/kg (maximum of 400 μg or 0.4 mL, 1:1,000) for treatment of mild-to-moderate allergic reactions or bronchospasm.
(ii) IV: Low-to-moderate dose (for shock, hypotension): 0.03 to 0.2 μg/kg bolus (IV), then infusion at 0.01 to 0.30 μg/kg/min.
High dose (for cardiac arrest, resuscitation): 0.5 to 1.0 mg IV bolus; pediatric, 5 to 15 μg/kg (may be given intratracheally in 1 to 10 mL volume). Larger doses are used when response to initial dose is inadequate.
Resuscitation doses of epinephrine may produce extreme hypertension, stroke, or myocardial infarction. A starting dose of epinephrine exceeding a 150 ng/kg (10 μg in an adult) IV bolus should be given only to a patient in extremis! Moderate doses (.03–.06 μg/kg/min) of epinephrine are commonly used to stimulate cardiac function an facilitate separation from cardiopulmonary bypass.
(b) Watch for signs of excessive vasoconstriction. Monitor SVR, renal function, extremity perfusion.
(c) Addition of a vasodilator (e.g., nicardipine, nitroprusside, or phentolamine) to epinephrine can counteract the α-mediated vasoconstriction, leaving positive cardiac inotropic effects undiminished. Alternatively, addition of milrinone or inamrinone may permit lower doses of epinephrine to be used. We find combinations of epinephrine and milrinone particularly useful in cardiac surgical patients.
f. NE (noradrenaline, Levophed)
See the preceding Section V: Vasopressors.
g. Isoproterenol (Isuprel)
(1) Isoproterenol is a synthetic catecholamine.
(a) Direct β1- plus β2-adrenergic agonist
(b) No α-adrenergic effects
(3) Offset. Rapid (half-life, 2 min); uptake by liver, conjugated, 60% excreted unchanged; metabolized by MAO, COMT
(a) Isoproterenol is a potent direct β-adrenergic receptor agonist.
(b) It increases CO by three mechanisms:
(i) Increased HR
(ii) Increased contractility S increased SV
(iii) Reduced afterload (SVR) S increased SV
(c) It is a bronchodilator (IV or inhaled).
(a) It is not a pressor! BP often falls (β2-adrenergic effect) while CO rises.
(b) Hypotension may produce organ hypoperfusion, hypotension, and ischemia.
(c) Tachycardia limits diastolic filling time.
(e) Dilates all vascular beds and is capable of shunting blood away from critical organs toward muscle and skin.
(f) Coronary vasodilation can reduce blood flow to ischemic myocardium while increasing flow to nonischemic areas producing coronary “steal” in patients with “steal-prone” coronary anatomy.
(g) May unmask pre-excitation in patients with an accessory AV conduction pathway (e.g., Wolff—Parkinson–White [WPW] syndrome).
(a) Bradycardia unresponsive to atropine when electrical pacing is not available
(b) Low CO, especially for situations in which increased inotropy is needed and tachycardia is not detrimental, such as the following:
(i) Pediatric patients with fixed SV
(ii) After resection of ventricular aneurysm (small fixed SV)
(iii) Denervated heart (after cardiac transplantation)
(c) Pulmonary hypertension or right heart failure
(d) AV block: Use as temporary therapy to decrease block or increase rate of idioventricular foci. Use with caution in second-degree Mobitz type II heart block—may intensify heart block.
(e) Status asthmaticus: Intravenous use mandates continuous ECG and BP monitoring.
(f) β-Blocker overdose
(g) Isoproterenol should not be used for cardiac asystole. CPR with epinephrine or pacing is the therapy of choice because isoproterenol-induced vasodilation results in reduced carotid and coronary blood flow during CPR.
(7) Administration. IV (safe through peripheral line, will not necrose skin); PO
(8) Clinical use and isoproterenol dose. IV infusion is 20 to 500 ng/kg/min.
2. PDE inhibitors
a. Inamrinone (Inocor) 
(1) Inamrinone is a bipyridine derivative that inhibits the cyclic guanosine monophosphate (cGMP)-inhibited cAMP-specific PDE III, increasing cAMP concentrations in cardiac muscle (positive inotropy) and in vascular smooth muscle (vasodilation).
(a) The elimination half-life is 2.5 to 4 h, increasing to 6 h in patients with CHF.
(b) Offset occurs by hepatic conjugation, with 30% to 35% excreted unchanged in urine.
(a) As a vasodilating inotrope, inamrinone increases CO by augmenting contractility and decreasing cardiac afterload.
(b) Favorable effects on MVO2 (little increase in HR; decreases afterload, LVEDP, and wall tension)
(c) It does not depend on activation of β-receptors and therefore retains effectiveness despite β-receptor downregulation or uncoupling (e.g., CHF) and in the presence of β-adrenergic blockade.
(d) Low risk of tachycardia or arrhythmias
(e) Inamrinone may act synergistically with β-adrenergic receptor agonists and dopaminergic receptor agonists.
(f) Pulmonary vasodilator
(g) Positive lusitropic properties (ventricular relaxation) at even very low dosages
(a) Thrombocytopenia after chronic (more than 24 h) administration
(b) Will nearly always cause hypotension from vasodilation if given by rapid bolus administration. Hypotension is easily treated with IV fluid and α agonists.
(c) Increased dosages may result in tachycardia (and therefore increased MVO2).
(d) Less convenient than milrinone because of photosensitivity and reduced potency
(5) Administration. IV infusion only. Do not mix in dextrose-containing solutions.
(6) Clinical use
(a) Inamrinone loading dose is 0.75 to 1.5 mg/kg. When given during or after CPB, usual dosage is 1.5 mg/kg.
(b) IV infusion dose range is 5 to 20 μg/kg/min (usual dosage is 10 μg/kg/min).
(c) Used in cardiac surgical patients in a manner similar to milrinone
(d) The popularity of this agent has steadily declined since the introduction of milrinone, largely due to milrinone’s lack of an adverse action on platelet function. Inamrinone is included here mostly for completeness.
b. Milrinone (Primacor) 
(a) Milrinone has powerful cardiac inotropic and vasodilator properties. Milrinone increases intracellular concentrations of cAMP by inhibiting its breakdown. Milrinone inhibits the cGMP-inhibited, cAMP-specific PDE (commonly known by clinicians as “type III”) in cardiac and vascular smooth-muscle cells. In cardiac myocytes, increased cAMP causes positive inotropy, lusitropy (enhanced diastolic myocardial relaxation), chronotropy, and dromotropy (AV conduction), as well as increased automaticity. In vascular smooth-muscle cells, increased cAMP causes vasodilation.
(b) Hemodynamic actions
(2) Onset and offset. When administered as an IV bolus, milrinone rapidly achieves its maximal effect. The elimination half-life of milrinone is considerably shorter than that of inamrinone.
(a) Used as a single agent, milrinone has favorable effects on the myocardial oxygen supply–demand balance, due to reduction of preload and afterload, and minimal tendency for tachycardia.
(b) Milrinone does not act via β-adrenergic receptors and it retains efficacy when β-adrenergic receptor coupling is impaired, as in CHF.
(c) It induces no tachyphylaxis.
(d) Milrinone has less proarrhythmic effects than β-adrenergic receptor agonists.
(e) When compared to dobutamine at equipotent doses, milrinone is associated with a greater decrease in PVR, greater augmentation of RV ejection fraction, less tachycardia, fewer arrhythmias, and lower MVO2.
(f) This drug may act synergistically with drugs that stimulate cAMP production, such as β-adrenergic receptor agonists.
(g) Even with chronic use, milrinone (unlike inamrinone) does not cause thrombocytopenia.
(a) Vasodilation and hypotension are predictable with rapid IV bolus doses.
(b) As with all other positive inotropic drugs, including epinephrine and dobutamine, independent manipulation of cardiac inotropy and SVR cannot be achieved using only milrinone.
(c) Arrhythmias may occur.
(5) Clinical use
(a) Milrinone loading dose: 25 to 75 (usual dose is 50) μg/kg given over 1 to 10 min. Often it is desirable to administer the loading dose before separating the patient from CPB so that hypotension can be managed more easily .
(b) Maintenance infusion: 0.375 to 0.75 μg/kg/min (usual maintenance is 0.5 μg/kg/min). Dosage should be reduced in renal failure.
(a) Low CO syndrome, especially in the setting of increased LVEDP, pulmonary hypertension, RV failure
(b) To supplement/potentiate β-adrenergic receptor agonists
(c) Outpatient milrinone infusion has been used as a bridge to cardiac transplantation.
a. Glucagon is a peptide hormone produced by the pancreas.
b. Actions. Glucagon increases intracellular cAMP, acting via a specific receptor.
c. Offset of action of glucagon occurs by redistribution and proteolysis by the liver, kidney, and plasma. Duration of action is 20 to 30 min.
d. Advantages. Glucagon has a positive inotropic effect even in the presence of β-blockade.
(1) Consistently produces nausea and vomiting
(3) Hyperglycemia and hypokalemia
(4) Catecholamine release from pheochromocytomas
(5) Anaphylaxis (possible)
f. Indications for glucagon include the following:
(1) Severe hypoglycemia (especially if no IV access) from insulin overdosage
(2) Spasm of sphincter of Oddi
(3) Heart failure from β-blocker overdosage
g. Administration. IV, IM, SC
h. Clinical use
(1) Glucagon dose: 1 to 5 mg IV slowly; 0.5 to 2 mg IM or SC.
(2) Infusion: 25 to 75 μg/min.
(3) Rarely used (other than for hypoglycemia) because of gastrointestinal side effects and severe tachycardia.
C. cAMP-independent agents
1. Calcium 
a. Calcium is physiologically active only as the free (unbound) calcium ion (Cai).
(1) Normally, approximately 50% of the total plasma calcium is bound to proteins and anions and the rest remains as free calcium ions.
(2) Factors affecting ionized calcium concentration:
(a) Alkalosis (metabolic or respiratory) decreases Cai.
(b) Acidosis increases Cai.
(c) Citrate binds (chelates) Cai.
(d) Albumin binds Cai.
(3) Normal plasma concentration: [Cai] = 1 to 1.3 mmol/L.
b. Actions of calcium salts
c. Offset. Calcium is incorporated into muscle and bone and binds to protein, free fatty acids released by heparin, and citrate.
(1) It has rapid action with duration of approximately 10 to 15 min (7 mg/kg dose).
(2) It reverses hypotension caused by the following conditions:
(a) Halogenated anesthetic overdosage
(b) Calcium-blocking drugs (CCBs)
(d) CPB, especially with dilutional or citrate-induced hypocalcemia, or when cardioplegia-induced hyperkalemia remains present (administer calcium salts only after heart has been well reperfused to avoid augmenting reperfusion injury)
(e) β-blockers (watch for bradycardia!)
(3) It reverses cardiac toxicity from hyperkalemia (e.g., arrhythmias, heart block, and negative inotropy).
(1) Minimal evidence that calcium salts administered to patients produce even a transient increase in CO.
(2) Calcium can provoke digitalis toxicity which can present as ventricular arrhythmias, AV block, or asystole.
(3) Calcium potentiates the effects of hypokalemia on the heart (arrhythmias).
(4) Severe bradycardia or heart block occurs rarely.
(5) When extracellular calcium concentration is increased while the surrounding myocardium is being reperfused or is undergoing ongoing ischemia, increased cellular damage or cell death occurs.
(6) Post-CPB coronary spasm may occur rarely.
(7) Associated with pancreatitis when given in large doses to patients recovering from CPB.
(8) Calcium may inhibit clinical responses to epinephrine and dobutamine .
f. Indications for use
(2) Hyperkalemia (to reverse AV block or myocardial depression)
(3) Intraoperative hypotension due to decreased myocardial contractility from hypocalcemia or calcium channel blockers
(4) Inhaled general anesthetic overdose
(5) Toxic hypermagnesemia
(1) Calcium chloride: IV, preferably by central line (causes peripheral vein inflammation and sclerosis).
(2) Calcium gluconate: IV, preferably by central line.
h. Clinical use
(1) Calcium dose
(a) 10% calcium chloride 10 mL (contains 272 mg of elemental calcium or 13.6 mEq): adult, 200 to 1,000 mg slow IV; pediatric, 10 to 20 mg/kg slow IV
(b) 10% calcium gluconate 10 mL (contains 93 mg of elemental calcium or 4.6 mEq): adult, 600 to 3,000 mg slow IV; pediatric, 30 to 100 mg/kg slow IV
(2) During massive blood transfusion (more than 1 blood volume replaced with citrate-preserved blood), a patient may receive citrate, which binds calcium. In normal situations, hepatic metabolism quickly eliminates citrate from plasma, and hypocalcemia does not occur. However, hypothermia and shock may decrease citrate clearance with resultant severe hypocalcemia. Rapid infusion of albumin will transiently reduce ionized calcium levels.
(3) Ionized calcium levels should be measured frequently to guide calcium salt therapy. Adults with an intact parathyroid gland quickly recover from mild hypocalcemia without treatment.
(4) Calcium is not recommended during resuscitation unless hypocalcemia, hyperkalemia, or hypermagnesemia are present.
(5) Calcium should be used with care in situations in which ongoing myocardial ischemia may be occurring or during reperfusion of ischemic tissue. “Routine” administration of large doses of calcium to all adult patients at the end of CPB is unnecessary and may be deleterious if the heart has been reperfused only minutes earlier.
(6) Hypocalcemia is frequent in children emerging from CPB.
2. Digoxin (Lanoxin)
a. Digoxin is a glycoside derived from the foxglove plant.
(1) Digoxin inhibits the integral membrane protein Na-K ATPase, causing Na+ accumulation in cells and increased intracellular Cai, which leads to increased Ca2+ release from the sarcoplasmic reticulum into the cytoplasm with each heartbeat, ultimately causing a mildly increased myocardial contractility.
(2) Hemodynamic effects
(b) Hemodynamics in CHF
c. Offset. Digoxin elimination half-life is 1.7 days (renal elimination). In anephric patients, half-life is more than 4 days.
(1) Supraventricular antiarrhythmic action
(2) Reduced ventricular rate in atrial fibrillation or flutter
(3) An orally active positive inotrope which is not associated with increased mortality in CHF
(1) Digoxin has an extremely low therapeutic index; 20% of patients show toxicity at some time.
(2) Increased MVO2 and SVR occur in patients without CHF (angina may be precipitated).
(3) The drug has a long half-life, and it is difficult to titrate.
(4) There is large interindividual variation in therapeutic and toxic serum levels and dosages. The dose response is nonlinear; near-toxic levels may be needed to achieve a change in AV conduction.
(5) Toxic manifestations may be life-threatening and difficult to diagnose. Digoxin can produce virtually any arrhythmia. For example, digitalis is useful in treating SVT, but digitalis toxicity can trigger SVT.
(6) Digoxin may be contraindicated in patients with accessory pathway SVT. Please refer to Digoxin use for SVT in Section VIII.E.
f. Indications for use
(1) Supraventricular tachyarrhythmias (see Section VIII.E)
(2) CHF (mostly of historical interest for this condition)
g. Administration. IV, PO, IM
h. Clinical use (general guidelines only)
(1) Digoxin dose (assuming normal renal function; decrease maintenance dosages with renal insufficiency)
(a) Adult: Loading dose IV and IM, 0.25 to 0.50 mg increments (total 1 to 1.25 mg or 10 to 15 μg/kg); maintenance dose, 0.125 to 0.250 mg/day based on clinical effect and drug levels
(b) Pediatric digoxin (IV administration)
(2) Digoxin has a gradual onset of action over 15 to 30 min or more; peak effect occurs 1 to 5 h after IV administration.
(3) Use with caution in the presence of β-blockers, calcium channel blockers, or calcium.
(4) Always consider the possibility of toxic side effects.
(a) Signs of toxicity include arrhythmias, especially with features of both increased automaticity and conduction block (e.g., junctional tachycardia with a 2:1 AV block). Premature atrial or ventricular depolarizations, AV block, accelerated junctional tachycardia, VT or VF (may be unresponsive to countershock), or gastrointestinal or neurologic toxicity may also be apparent.
(5) Factors potentiating toxicity
(a) Hypokalemia, hypomagnesemia, hypercalcemia, alkalosis, acidosis, renal insufficiency, quinidine therapy, and hypothyroidism may potentiate toxicity.
(b) Beware of administering calcium salts to digitalized patients! Malignant ventricular arrhythmias (including VF) may occur, even if the patient has received no digoxin for more than 24 h. Follow ionized calcium levels to permit use of smallest possible doses of calcium.
(6) Therapy for digitalis toxicity
(a) Increase serum [K+] to upper limits of normal (unless AV block is present).
(b) Treat ventricular arrhythmias with phenytoin, lidocaine, or amiodarone.
(c) Treat atrial arrhythmias with phenytoin or amiodarone.
(d) β-Blockers are effective for digoxin-induced arrhythmias, but ventricular pacing may be required if AV block develops.
(e) Beware of cardioversion. VF refractory to countershock may be induced. Use low-energy synchronized cardioversion and slowly increase energy as needed.
(7) Serum digoxin levels
(a) Therapeutic: Approximately 0.5 to 2.5 ng/mL. Values of less than 0.5 ng/mL rule out toxicity. Values exceeding 3 ng/mL are definitely toxic.
(b) Increased serum concentrations may not produce clinical toxicity in children or hyperkalemic patients, or when digitalis is used as an atrial antiarrhythmic agent.
(c) “Therapeutic” serum concentrations may produce clinical toxicity in patients with hypokalemia, hypomagnesemia, hypercalcemia, myocardial ischemia, hypothyroidism, or those recovering from CPB.
(8) Because of its long duration of action, long latency of onset, and increased risk of toxicity, digoxin is not used to treat acute heart failure.
(9) For all indications, digoxin is much less widely used in recent years.
3. Triiodothyronine (T3, liothyronine IV) . T3 is the active form of thyroid hormone. It has multiple cellular actions on the nucleus and on mitochondria, affecting gene transcription and oxidative phosphorylation. There is evidence that CPB induces a state of low plasma thyrotropin (T3), termed the “euthyroid sick” syndrome. Laboratory studies demonstrate that T3 stimulates cardiac inotropy and lusitropy even in the face of overwhelming β-adrenergic receptor blockade and without increasing intracellular concentrations of cAMP. Despite reports that liothyronine would facilitate the separation from CPB of patients who could not be weaned using conventional therapies, larger clinical trials failed to identify efficacy of T3. Doses that have been suggested include a bolus of 0.4 μg/kg IV followed by 0.4 μg/kg infused over 6 h. T3 is advocated over thyroxine because of the very slow onset time of the latter hormone and the reduced ability of critically ill patients to convert T4 to T3. In treatment of myxedema coma, corticosteroids should be given with liothyronine.
4. Levosimendan 
(1) Binds in Ca-dependent manner to cardiac troponin C, shifting the Ca2+ tension curve to the left. Levosimendan may stabilize Ca2+-induced confirmational changes in troponin C.
(2) Its effects are maximized during early systole when intracellular Ca2+ concentration is greatest and least during diastolic relaxation when Ca2+ concentration is low.
(3) Levosimendan also inhibits PDE III activity.
(4) Hemodynamic actions
(1) Does not increase intracellular Ca2+
(2) Does not work via cAMP so should not interact with β agonists or PDE inhibitors
(1) Unknown potency relative to other agents
(2) Has not received regulatory approval in major North American or Western European countries
Where approved, drug’s indications include acute heart failure and acute exacerbations of CHF.
f. Clinical use
(1) 8 to 24 μg/kg/min
(2) Despite its biochemical actions on PDE, levosimendan is not associated with increased cAMP, so it may have reduced tendency for arrhythmias relative to sympathomimetics.
VII. β-Adrenergic receptor–blocking drugs [3,5]
A. Actions. These drugs bind and antagonize β-adrenergic receptors typically producing the following cardiovascular effects:
B. Advantages of β-adrenergic-blocking drugs
1. Reduce MVO2 and decrease HR and contractility
2. Increase the duration of diastole, during which majority of blood flow and oxygen are delivered to the left ventricle.
3. Synergistic with nitroglycerin for treating myocardial ischemia; blunt reflex tachycardia and increased contractility secondary to nitroglycerin, nitroprusside, or other vasodilator drugs
4. Have an antiarrhythmic action, especially against atrial arrhythmias
5. Decrease LV ejection velocity (useful in patients with aortic dissection)
6. Antihypertensive, but should not be first-line agents for essential hypertension
7. Reduce dynamic ventricular outflow tract obstruction (e.g., tetralogy of Fallot, hypertrophic cardiomyopathy)
8. Use of these agents is associated with reduced mortality after myocardial infarction, chronic angina, CHF, and hypertension.
1. Severe bradyarrhythmias are possible.
2. Heart block (first, second, or third degree) may occur, especially if prior cardiac conduction abnormalities are present, or when IV β-blockers and certain IV calcium channel blockers are coadministered.
3. May trigger bronchospasm in patients with reactive airways
4. CHF can occur in patients with low ejection fraction newly receiving large doses. Elevated LVEDP may induce myocardial ischemia because of elevated systolic wall tension.
5. Signs and symptoms of hypoglycemia (except sweating) are masked in diabetics.
6. SVR may increase because of inhibition of β2 vasodilation; use with care in patients with severe peripheral vascular disease or in patients with pheochromocytoma without α-blockade treatment.
7. Risk of coronary artery spasm is present in rare susceptible patients.
8. Acute perioperative withdrawal of β-blockers can lead to hyperdynamic circulation and myocardial ischemia.
D. Distinguishing features of β-blockers (Table 2.3)
1. Selectivity. Selective β-blockers possess a greater potency for β1- than for β2-receptors. They are less likely to cause bronchospasm or to increase SVR than a nonselective drug. However, β1 selectivity is dose-dependent (drugs lose selectivity at higher dosages). Caution must be exercised when an asthmatic patient receives any β-blocker.
2. Intrinsic sympathomimetic activity (ISA). These drugs possess “partial agonist” activity. Thus, drugs with ISA will block β-receptors (preventing catecholamines from binding to a receptor) but also will cause mild stimulation of the same receptors. A patient receiving a drug with ISA would be expected to have a greater resting HR and CO (which shows no change with exercise) but a lower SVR compared to a drug without ISA.
3. Duration of action. In general, the β-blockers with longer durations of action are eliminated by the kidneys, whereas the drugs of 4 to 6 h duration undergo hepatic elimination. Esmolol, the ultrashort–acting β-blocker (plasma half-life, 9 min), is eliminated within the blood by a red blood cell esterase. After abrupt discontinuation of esmolol infusion (which under most circumstances we do not recommend), most drug effects are eliminated within 5 min. The duration of esmolol does not change when plasma pseudocholinesterase is inhibited by echothiophate or physostigmine.
E. Clinical use
1. β-Blocker dosage
a. See Table 2.3.
b. Begin with a low dose and slowly increase until desired effect is produced.
c. For metoprolol IV dosage use 1 to 5 mg increments (for adults) as tolerated while monitoring the ECG, BP, and lung sounds. Intravenous dosage is much smaller than oral dosage because first-pass hepatic extraction is bypassed. The usual acute IV metoprolol dose is 0.02 to 0.1 mg/kg.
2. If β-blockers must be given to a patient with bronchospastic disease, choose a selective β1 blocker such as metoprolol or esmolol and consider concomitant administration of an inhalation β2 agonist (such as albuterol).
3. Treatment of toxicity. β-agonists (e.g., isoproterenol, possibly in large doses) and cardiac pacing are the mainstays. Calcium, milrinone, inamrinone, glucagon, or liothyronine may be effective because these agents do not act via β-receptors.
4. Assessment of β-blockade. When β-blockade is adequate, a patient should not demonstrate an increase in HR with exercise.
5. Use of αagonists in β-blocked patients. When agonist drugs with α or both α and β actions are administered to patients who are β-blocked, e.g., with an epinephrine-containing IV local anesthetic test dose, a greater elevation of BP can be expected owing to α vasoconstriction unopposed by β2 vasodilation. This may produce deleterious hemodynamic results (increased afterload with little increased CO).
6. Esmolol is given by IV injection (loading dose), often followed by continuous infusion. (For details on esmolol dosing for SVT, see Section VIII.E.) It is of greatest utility when the required duration of β-blockade is short (i.e., to attenuate a short-lived stimulus). Esmolol’s ultrashort duration of action plus its β1 selectivity and lack of ISA make it a logical choice when it is necessary to initiate a β-blocker in patients with asthma or another relative contraindication. It is also useful in critically ill patients with changing hemodynamic status.
Table 2.3 β-Adrenergic–blocking drugs
7. Labetalol is a combined α and β antagonist (α/β ratio = 1:7), which produces vasodilation without reflex tachycardia. Labetalol is useful for preoperative or postoperative control of hypertension. During anesthesia, its relatively long duration of action makes it less useful than other agents for minute-to-minute control of HR and BP. However, treatment with labetalol or another β-adrenergic receptor antagonist will reduce the needed dosage of short-acting vasodilators.
8. β-Adrenergic receptor antagonist withdrawal. Abrupt withdrawal of chronic β-blocker therapy may produce a withdrawal syndrome including tachycardia and hypertension. Myocardial ischemia or infarction may result. Thus, chronic β-blocker therapy should not be abruptly discontinued perioperatively. The authors have seen this syndrome complete with myocardial ischemia after abrupt discontinuation of esmolol when it had been infused for only 48 h!
9. Certain β-adrenergic receptor blockers are now part of the standard therapy of patients with Class B through Class D CHF. The drugs most often used are carvedilol and metoprolol-XL, and these agents have been shown to prolong survival in heart failure. β-adrenergic receptor blocker therapy is associated with improved LV function and improved exercise tolerance over time. These agents counteract the sympathetic nervous system activation that is present with CHF. In animal studies, β-adrenergic receptor blocker therapy reduces “remodeling,” which is the process by which functional myocardium is replaced by connective tissue. Importantly, not all β-adrenergic receptor blockers have been shown to improve outcome in CHF, so reduced mortality should not be considered a “class effect” of β-adrenergic receptor blockers.
F. Specific agents
1. See Table 2.3.
VIII. Vasodilator drugs 
1. Sites of action
2. Mechanisms of action
a. Direct vasodilators: Calcium channel blockers, hydralazine, minoxidil, nitroglycerin, nitroprusside.
b. α-adrenergic blockers: Labetalol, phentolamine, prazosin, terazosin, tolazoline.
c. Ganglionic blocker: Trimethaphan.
d. ACE inhibitor: Enalaprilat, captopril, enalapril, lisinopril.
e. ARBs: Candesartan, irbesartan, losartan, olmesartan, valsartan, telmisartan.
f. Central α2 agonists (reduce sympathetic tone): Clonidine, guanabenz, guanfacine.
g. Calcium channel blockers (see Section VII)
h. Nesiritide: Binds to natriuretic factor receptors.
3. Indications for use
a. Hypertension, increased SVR states. Use arterial or mixed drugs. First-line agent for long-term treatment of essential hypertension should be thiazide diuretic with ACE inhibitors, ARBs, calcium channel blockers, β-blockers, as secondary choices. Other oral agents are not associated with outcome benefit.
b. Controlled hypotension. Short-acting drugs are most useful (e.g., nitroprusside, nitroglycerine, nicardipine, clevidipine, nesiritide, and volatile inhalational anesthetics).
c. Aortic valvular regurgitation. Reducing SVR will tend to improve oxygen delivery to tissues.
d. CHF. Vasodilation reduces MVO2 by lowering preload and afterload (systolic wall stress, due to reduced LV size and pressure). Vasodilation also improves ejection and compliance. More importantly, ACE inhibitors and ARBs inhibit “remodeling” and increase longevity in patients with heart failure.
e. Thermoregulation. Vasodilators are often used during the cooling and rewarming phases of CPB to facilitate tissue perfusion and accelerate temperature equilibration. This is especially important during pediatric CPB procedures and others involving total circulatory arrest where an increased CBF promotes brain cooling and brain protection during circulatory arrest.
f. Pulmonary hypertension. Vasodilators can improve pulmonary hypertension that is not anatomically fixed. Presently, inhaled NO is the only truly selective pulmonary vasodilator.
g. Myocardial ischemia. Vasodilator therapy can improve myocardial O2 balance by reducing MVO2 (decreased preload and afterload), and nitrates and calcium channel blockers can dilate conducting coronary arteries to improve the distribution of myocardial blood flow. ACE inhibitors prolong lifespan in patients who have had a myocardial infarction.
h. Intracardiac shunts. Vasodilators are used in the setting of nonrestrictive cardiac shunts, especially ventricular septal defects and aortopulmonary connections, to manipulate the ratio of pulmonary artery to aortic pressures. This allows control of the direction and magnitude of shunt flow.
a. Hyperdynamic reflexes. All vasodilator drugs decrease SVR and BP and may activate baroreceptor reflexes. This cardiac sympathetic stimulation produces tachycardia and increased contractility. Myocardial ischemia resulting from increased myocardial O2 demands can be additive to ischemia produced by reduced BP. Addition of a β-blocker can attenuate these reflexes.
b. Ventricular ejection rate. Reflex sympathetic stimulation will also increase the rate of ventricular ejection of blood (dP/dt) and raise the systolic aortic wall stress. This may be detrimental with aortic dissection. Thus, addition of β-blocker (or a ganglionic blocker) is of theoretical benefit for patients with aortic dissection, aortic aneurysm, or recent aortic surgery.
c. Stimulation of the renin–angiotensin system is implicated in the “rebound” increased SVR and PVR when some vasodilators are discontinued abruptly. Renin release can be attenuated by concomitant β-blockade, and renin’s actions are attenuated by ACE inhibitors and ARBs.
d. Intracranial pressure (ICP). Most vasodilators will increase ICP, except for trimethaphan and fenoldopam.
e. Use of nesiritide for decompensated CHF was associated with increased mortality.
B. Specific agents
1. Direct vasodilators
a. Hydralazine (Apresoline)
(a) This drug is a direct vasodilator.
(b) It primarily produces an arteriolar dilatation, with little venous (preload) effect.
(2) Offset occurs by acetylation in the liver. Patients who are slow acetylators (up to 50% of the population) may have higher plasma hydralazine levels and may show a longer effect, especially with oral use.
(a) Selective vasodilation. Hydralazine produces more dilation of coronary, cerebral, renal, and splanchnic beds than of vessels in the muscle and skin.
(b) Maintenance of uterine blood flow (if hypotension is avoided).
(a) Slow onset (5 to 15 min) after IV dosing; peak effect should occur by 20 min. Thus, at least 10 to 15 min should separate doses.
(b) Reflex tachycardia or coronary steal can precipitate myocardial ischemia.
(c) A lupus-like reaction, usually seen only with chronic PO use, may occur with chronic high doses (more than 400 mg/day) and in slow acetylators.
(5) Clinical use
(a) Hydralazine dose
(i) IV: 2.5 to 5 mg bolus every 15 min (maximum 20 to 40 mg)
(ii) IM: 20 to 40 mg every 4 to 6 h
(iii) PO: 10 to 50 mg every 6 h
(iv) Pediatric dose: 0.2 to 0.5 mg/kg IV every 4 to 6 h, slowly
(b) Slow onset limits use in acute hypertensive crises.
(c) Doses of vasodilators can be reduced by the addition of hydralazine, decreasing the risk of cyanide toxicity from nitroprusside or prolonged ganglionic blockade from trimethaphan.
(d) Addition of a β-blocker attenuates reflex tachycardia.
(e) Patients with CAD should be monitored for myocardial ischemia.
(f) Enalaprilat, nicardipine, and labetalol are replacing hydralazine for many perioperative applications.
b. Nitroglycerin (glyceryl trinitrate) 
(a) Nitroglycerin is a direct vasodilator, producing greater venous than arterial dilation. A nitric acid-containing metabolite activates vascular cGMP production.
(b) Peripheral venous effects. Venodilation and peripheral pooling reduce effective blood volume, decreasing heart size and preload. This effect usually reduces MVO2 and increases diastolic coronary blood flow.
(c) Coronary artery
(i) Relieves coronary spasm.
(ii) Flow redistribution provides more flow to ischemic myocardium and increases endocardial-to-epicardial flow ratio.
(iii) There is increased flow to ischemic regions through collateral vessels.
(d) Myocardial effects
(i) Improved inotropy due to reduced ischemia
(ii) Indirect antiarrhythmic action (VF threshold increases in ischemic myocardium because the drug makes the effective refractory period more uniform throughout the heart)
(e) Arteriolar effects (higher dosages only)
(i) Arteriolar dilatation decreases SVR. With reduced systolic myocardial wall stress, MVO2 decreases, and ejection fraction and SV may improve.
(ii) Arteriolar dilation often requires large doses, exceeding 10 μg/kg/min in some patients, whereas much lower doses give effective venous and coronary arterial dilating effects. When reliable peripheral arteriolar dilation is needed to control a hypertensive emergency, nicardipine, nitroprusside, or clevidipine are often better choices (and can be used together with nitroglycerin).
(2) Offset occurs by redistribution, metabolism in smooth muscle and liver. Half-life in humans is 1 to 3 min.
(a) Preload reduction (lowers LV and RV end-diastolic and LA and RA pressures)
(b) Unlike nitroprusside, virtually no metabolic toxicity
(c) Effective for myocardial ischemia
(i) Decreases infarct size after coronary occlusion
(ii) Maintains arteriolar autoregulation, so coronary steal unlikely
(d) Useful in acute exacerbations of CHF to decrease preload and reduce pulmonary vascular congestion
(e) Increases vascular capacity; may permit infusion of residual pump blood after CPB is terminated
(f) Not as photosensitive as nitroprusside
(g) Dilates the pulmonary vascular bed and can be useful in treating acute pulmonary hypertension and right heart failure
(h) Attenuates biliary colic and esophageal spasm
(a) It decreases BP as preload and SVR decrease at higher dosages. This may result in decreased coronary perfusion pressure.
(b) Reflex tachycardia and reflex increase in myocardial contractility are dose-related. Consider reducing dose or administering a β-blocker (if BP is satisfactory).
(c) It inhibits hypoxic pulmonary vasoconstriction (but to a lesser extent than nitroprusside). Monitor PO2 or supplement inspired gas with oxygen.
(d) It may increase ICP.
(e) It is adsorbed by polyvinyl chloride IV tubing. Titrate dosage to effect; increased effect may occur when tubing becomes saturated. Special infusion sets that do not adsorb drug are expensive and unnecessary.
(f) Tolerance. Chronic continuous therapy (for longer than 24 h) can blunt hemodynamic and antianginal effects. Tolerance during chronic therapy may be avoided by discontinuing the drug (if appropriate) for several hours daily.
(g) Dependence. Coronary spasm and myocardial infarction have been reported after abrupt cessation of chronic industrial exposure.
(h) Methemoglobinemia. Avoid administering doses greater than 7 to 10 μg/kg/min for prolonged periods.
(5) Clinical use
(a) Nitroglycerin dose
(i) IV bolus: A bolus dose of 50 to 100 μg may be superior to infusion for acute ischemia. Rapidly changing levels in blood may cause more vasodilation than a constant infusion (and thus may be more likely to produce hypotension).
(ii) Infusion: Dose range, 0.1 to 7 μg/kg/min.
(iii) Sublingual: 0.15 to 0.60 mg.
(iv) Topical: 2% ointment (Nitropaste), 0.5 to 2 in. every 4 to 8 h; or controlled-release transdermal preparation (Transderm-Nitro, Nitrodisc), 5 to 10 mg (or more) every 24 h or as needed.
(b) Unless non-polyvinyl chloride tubing is used, infusion requirements may decrease after the initial 30 to 60 min.
(c) Nitroglycerin is better stored in bottles than in bags if storage for more than 6 to 12 h is anticipated.
(d) When administered during CPB, venous pooling may cause decreases in pump reservoir volume.
c. Nitroprusside (Nipride) [16,20]
(a) Nitroprusside (SNP) is a direct-acting vasodilator. The nitrate group is converted into NO in vascular smooth muscle, which causes increased cGMP levels in cells.
(b) It has balanced arteriolar and venous dilating effects.
(a) SNP has a very short duration of action (1 to 2 min) permitting precise titration of dose.
(b) It has pulmonary vasodilator in addition to systemic vasodilator effects.
(c) SNP is highly effective for virtually all causes of hypertension except high CO states.
(d) A greater decrease in SVR (afterload) than preload is produced at low dosages.
(a) Cyanide and thiocyanate toxicity may occur.
(b) SNP solution is unstable in light and so must be protected from light. Photodecomposition inactivates nitroprusside over many hours but does not release cyanide ion.
(c) Reflex tachycardia and increased inotropy (undesirable with aortic dissection because of increased shearing forces) respond to β-blockade.
(d) Hypoxic pulmonary vasoconstriction is blunted and may produce arterial hypoxemia from increased venous admixture.
(e) Vascular steal. All vascular regions are dilated equally. Although total organ blood flow may increase, flow may be diverted from ischemic regions (previously maximally vasodilated) to nonischemic areas that, prior to SNP exposure, were appropriately vasoconstricted. Thus, myocardial ischemia may be worsened. However, severe hypertension is clearly dangerous in ischemia, and the net effect often is beneficial. ECG monitoring is important.
(f) Patients with chronic hypertension may experience myocardial, cerebral, or renal ischemia with abrupt lowering of BP to “normal” range.
(g) Rebound systemic or pulmonary hypertension may occur if SNP is stopped abruptly (especially in patients with CHF). SNP should be tapered.
(h) Mild preload reduction due to venodilation occurs; fluids often must be infused if CO falls.
(i) Risk of increased ICP (although ICP often decreases with control of hypertension)
(j) Platelet function is inhibited (no known clinical consequences).
(a) Chemical formula of SNP is Fe(CN)5NO. SNP reacts with hemoglobin to release highly toxic free cyanide ion (CN–).
(b) SNP + oxyhemoglobin S four free cyanide ions + cyanomethemoglobin (nontoxic).
(c) Cyanide ion produces inhibition of cytochrome oxidase, preventing mitochondrial oxidative phosphorylation. This produces tissue hypoxia despite adequate PO2.
(d) Cyanide detoxification
(i) Cyanide + thiosulfate (and rhodanase) S thiocyanate. Thiocyanate is much less toxic than cyanide ion. Availability of thiosulfate is the rate-limiting step in cyanide metabolism. Adults can typically detoxify 50 mg of SNP using existing thiosulfate stores. Thiosulfate administration is of critical importance in treating cyanide toxicity. Rhodanase is an enzyme found in liver and kidney that promotes cyanide detoxification.
(ii) Cyanide + hydroxocobalamin S cyanocobalamin (vitamin B12).
(e) Patients at increased risk of toxicity:
(i) Those resistant to vasodilating effects at low SNP dosages (requiring dose greater than 3 μg/kg/min is necessary for effect)
(ii) Those receiving a high-dose SNP infusion (greater than 8 μg/kg/min) for any period of time. In this setting, frequent blood gas measurements must be performed, and consideration must be given to the following:
(a) First and foremost, decrease dosage by adding another vasodilator or a β-blocker.
(b) Consider monitoring mixed venous oxygenation (see Section f.2).
(iii) Those receiving a large total dose (greater than 1 mg/kg) over 12 to 24 h
(iv) Those with either severe renal or hepatic dysfunction
(f) Signs of SNP toxicity
(i) Tachyphylaxis occurs in response to vasodilating effects of SNP.
(ii) Elevated mixed venous PO2 (due to decreased cellular O2 utilization) occurs in the absence of a rise in CO.
(iii) There is metabolic acidosis.
(iv) No cyanosis is seen with cyanide toxicity (cells cannot utilize O2; therefore, blood O2 saturation remains high).
(v) Chronic SNP toxicity is due to elevated thiocyanate levels and is a consequence of long-term therapy or thiocyanate accumulation in renal failure. Thiocyanate is excreted unchanged by the kidney (elimination half-life, 1 wk). Elevated thiocyanate levels (greater than 5 mg/dL) can cause fatigue, nausea, anorexia, miosis, psychosis, hyperreflexia, and seizures.
(g) Therapy of cyanide toxicity
(i) Cyanide toxicity should be suspected when a metabolic acidosis or unexplained rise in mixed venous PO2 appears in any patient receiving SNP.
(ii) As soon as toxicity is suspected, SNP must be discontinued and substituted with another agent; lowering the dosage is not sufficient because clinically evident toxicity implies a marked reduction in cytochrome oxidase activity.
(iii) Ventilate with 100% O2.
(iv) Treat severe metabolic acidosis with bicarbonate.
(v) Mild toxicity (base deficit less than 10, stable hemodynamics when SNP stopped) can be treated by sodium thiosulfate, 150 mg/kg IV bolus (hemodynamically benign).
(vi) Severe toxicity (base deficit greater than 10, or worsening hemodynamics despite discontinuation of nitroprusside:
(a) Create methemoglobin that can combine with cyanide to produce nontoxic cyanomethemoglobin, removing cyanide from cytochrome oxidase:
(1) Give 3% sodium nitrite, 4 to 6 mg/kg by slow IV infusion. (repeat one-half dose 2 to 48 h later as needed), or
(2) Give amyl nitrite: Break 1 ampule into breathing bag. (Flammable!)
(b) Sodium thiosulfate, 150 to 200 mg/kg IV over 15 min, should also be administered to facilitate metabolic disposal of the cyanide. Note that thiocyanate clearance is renal dependent.
(c) Consider hydroxocobalamin (vitamin B12) 25 mg/h.
Note: These treatments should be administered even during CPR; otherwise, O2 cannot be utilized by body tissues.
(5) Clinical use
(a) SNP dose: 0.1 to 2 μg/kg/min IV infusion. Titrate dose to BP and CO. Avoid doses greater than 2 μg/kg/min: Doses as high as 10 μg/kg/min should be infused for no more than 10 min.
(b) Monitor oxygenation.
(c) Solution in a bottle or bag must be protected from light by wrapping in metal foil. Solution stored in the dark retains significant potency for 12 to 24 h. It is not necessary to cover the administration tubing with foil.
(d) Because of the potency of SNP, it is best administered by itself into a central line using an infusion pump. If other drugs are being infused through the same line, use sufficient “carrier” flow so that changes in one drug’s infusion rate does not change the quantity of other drugs entering the patient per minute.
(e) Infusions should be tapered gradually to avoid rebound increases in systemic and PA pressures.
(f) Use this drug cautiously in patients with concomitant untreated hypothyroidism or severe liver or kidney dysfunction.
(g) Continuous BP monitoring with an arterial catheter is recommended.
(a) NO is a vasoactive gas naturally produced from L-arginine primarily in endothelial cells. Before its molecular identity was determined it was known as endothelium-derived relaxing factor.NO diffuses from endothelial cells to vascular smooth muscle, where it increases cGMP and affects vasodilation, in part by decreasing cytosolic calcium. It is an important physiologic intercellular signaling substance and NO or its absence is implicated in pathologic conditions such as reperfusion injury and coronary vasospasm.
(b) It is inhaled to treat pulmonary hypertension, particularly in respiratory distress syndrome in infancy.
(2) Offset. NO rapidly and avidly binds to the heme moiety of hemoglobin, forming the inactive compound nitrosylhemoglobin, which in turn degrades to methemoglobin. NO’s biologic half-life in blood is approximately 6 s.
(a) Inhaled NO appears to be the long-sought “selective” pulmonary vasodilator. It is devoid of systemic actions.
(b) Unlike parenterally administered pulmonary vasodilators, inhaled NO favorably affects lung V/Q relationships, because it vasodilates primarily those lung regions that are well ventilated.
(c) There is low toxicity, provided safety precautions are taken.
(a) Stringent safety precautions are required to prevent potentially severe toxicity, such as overdose or catastrophic nitrogen dioxide-induced pulmonary edema.
(b) Methemoglobin concentrations may reach clinically important values, and blood levels must be monitored daily.
(c) Chronic administration may cause ciliary depletion and epithelial hyperplasia in terminal bronchioles.
(d) NO is corrosive to metal.
(5) Clinical use
(a) NO is inhaled by blending dilute NO gas into the ventilator inlet gas. Therapeutic concentrations range from 0.05 to 80 parts per million (ppm). The lowest effective concentration should be used, and responses should be carefully monitored. The onset of action for reducing PVR and RVSWI is typically 1 to 2 min.
(b) NO must be purchased prediluted in nitrogen in assayed tanks, and an analyzer must be used intermittently to assay the gas stream entering the patient for NO and nitrogen dioxide. NO usually is not injected between the ventilator and the patient (to avoid overdose), and it must never be allowed to contact air or oxygen until it is used (to prevent formation of toxic nitrogen dioxide).
(c) NO has been used to treat persistent pulmonary hypertension of the newborn, other forms of pulmonary hypertension, and the adult respiratory distress syndrome with variable success and to date no effect on outcomes.
e. Nesiritide 
(a) Nesiritide binds to A and B natriuretic peptide receptors on endothelium and vascular smooth muscle, producing dilation of both arterial and venous systems from increased production of cGMP. It also has indirect vasodilating actions by suppressing the sympathetic nervous system, the renin–angiontensin–aldosterone system, and endothelin.
(b) Diuretic and natriuretic effects. Although nesiritide as a “cardiac natriuretic peptide” would be expected to have major diuretic and natriuretic effects, the agent seems most effective at this in healthy patients.
(c) Nisertide may be hydrolyzed by neutral endopeptidase. A small amount of administered drug may be eliminated via the kidneys.
(2) Current clinical use. Initial studies suggested that use of nesiritide was associated with reduced mortality in HF patients compared to the use of standard positive inotropic agents. The most recent data from a large clinical trial demonstrated that nesiritide offered no advantage over standard agents for acute decompensated HF.
(a) Typical doses are as follows:
(i) 2 μg/kg loading dose
(ii) 0.01 μg/kg/min maintenance infusion
2. α-Adrenergic blockers [3,5]
a. Labetalol (Normodyne, Trandate)
See preceding β-adrenergic receptor blocker section in which this agent was presented.
b. Phentolamine (Regitine)
(a) Competitive antagonist at α1, α2, and 5-hydroxytryptamine (5-HT, serotonin) receptors
(b) Primarily arterial vasodilation with little venodilation
(2) Offset occurs by hepatic metabolism, in part by renal excretion. Offset after IV bolus occurs after 10 to 30 min.
(a) Good for high NE states such as pheochromocytoma.
(b) Antagonizes undesirable α stimulation. For example, reversal of deleterious effects of NE extravasated into skin is achieved by local infiltration with phentolamine, 5 to 10 mg in 10 mL saline.
(c) Has been combined with NE for positive inotropic support with reduced vasoconstriction after CPB.
(a) Tachycardia arises from two mechanisms:
(i) Reflex via baroreceptors
(ii) Direct effect of α2 blockade. Blockade of presynaptic receptors eliminates the normal feedback system controlling NE release by presynaptic nerve terminals. As α2 stimulation decreases NE release, blockade of these receptors allows increased presynaptic release. This results in increased β1 sympathetic effects only, as the α-receptors mediating postsynaptic α effects are blocked by phentolamine. Myocardial ischemia or arrhythmias may result. Thus, the tachycardia and positive inotropy are β effects that will respond to β-blockers.
(b) Gastrointestinal motility is stimulated and gastric acid secretion increased.
(c) Hypoglycemia may occur.
(d) Epinephrine may cause hypotension in α-blocked patients (“epinephrine reversal”) via a β2 mechanism.
(e) Arrhythmias occur.
(f) There is histamine release.
(5) Clinical use
(a) Phentolamine dose
(i) IV bolus: 1 to 5 mg (adult) or 0.1 mg/kg IV (pediatric)
(ii) IV infusion: 1 to 20 μg/kg/min
(b) When administered for pheochromocytoma, β blockade may also be instituted.
(c) β-Blockade will attenuate tachycardia.
(d) Phentolamine has been used to promote uniform cooling of infants during CPB prior to DHCA (dose, 0.1 to 0.5 mg/kg).
c. Phenoxybenzamine (Dibenzyline)
(a) Noncompetitive antagonist at α1 and α2-receptors
(b) Primarily arterial vasodilation with little venodilation
(2) Offset occurs by hepatic metabolism, in part by renal excretion. Offset after IV bolus occurs after 10 to 30 min.
(a) Used for high NE states such as pheochromocytoma
(b) Given PO to prepare patients for excision of pheochromocytoma
(c) Slow onset and prolonged duration of action (half-life of roughly 24 h)
(a) Tachycardia arises from two mechanisms:
(i) Reflex via baroreceptors
(ii) Direct effect of α2 blockade. Blockade of presynaptic receptors eliminates the normal feedback system controlling NE release by presynaptic nerve terminals. As α2 stimulation decreases NE release, blockade of these receptors allows increased presynaptic release. This results in increased β1 sympathetic effects only, as the α-receptors mediating postsynaptic α effects are blocked by phentolamine. Myocardial ischemia or arrhythmias may result. Thus, the tachycardia and positive inotropy are β effects that will respond to β-blockers.
(b) “Stuffy” nose and headache are common.
(c) Creates marked apparent hypovolemia; adequate preoperative rehydration may result in marked postoperative edema.
(d) No IV form
(5) Clinical use
(a) Phenoxybenzamine dose
(i) PO dose: 10 mg (adult) bid.
(ii) Increase dose gradually up to 30 mg tid—limited by onset of side effects or by elimination of hypertension.
(b) When administered for pheochromocytoma, β-blockade should not be added until phenoxybenzamine dose has reached a steady state, unless there is exaggerated tachycardia or myocardial ischemia.
(c) Some authors advocate doxazosin or calcium channel blockers rather than phenoxybenzamine for preoperative preparation of pheochromocytoma, arguing that there are fewer side effects (preoperatively and postoperatively) with these agents.
d. Prazosin, doxazosin, and terazosin
(1) Actions. A selective α1 competitive antagonist, prazosin’s main cardiovascular action is vasodilation (arterial and venous) with decreased SVR and decreased preload. Reflex tachycardia is minimal.
(2) Offset occurs by hepatic metabolism. The half-life is 4 to 6 h.
(a) Virtual absence of tachycardia
(b) The only important cardiovascular action is vasodilation.
(4) Disadvantages. Postural hypotension with syncope may occur, especially after the initial dose.
(5) Indications. Oral treatment of chronic hypertension (but is not a first-line agent).
(6) Administration. PO
(7) Clinical use
(a) Prazosin dose: Initially 0.5 to 1 mg bid (maximum 40 mg/day).
(b) Prazosin is closely related to two other α1-blockers with which it shares a common mechanism of action:
(i) Doxazosin (Cardura). Half-life: 9 to 13 h. Dose: 1 to 4 mg/day (maximum 16 mg/day).
(ii) Terazosin (Hytrin). Half-life: 8 to 12 h. Dose: 1 to 5 mg/day (maximum 20 mg/day).
e. Tolazoline (Priscoline)
(a) Tolazoline, an imidazoline derivative, is a competitive α-adrenergic antagonist belonging to the same family as phentolamine.
(b) In addition to blocking α1- and α2-receptors, tolazoline also stimulates muscarinic cholinergic receptors (enhancing gastrointestinal motility and salivary secretions), causes histamine release from mast cells, and displays a sympathomimetic effect.
(2) Offset occurs by hepatic metabolism and renal excretion, with a half-life in neonates of 3 to 10 h.
(a) Tolazoline is not a selective pulmonary vasodilator. Generally, substantial systemic vasodilation occurs also, with hypotension. If PVR is fixed and SVR decreases, then the PVR/SVR ratio actually may increase.
(b) Sympathomimetic effect (possibly due to enhanced neuronal NE release) plus reflex sympathetic activation lead to marked tachycardia and arrhythmias. Pulmonary vasoconstriction may occur in some patients.
(c) Peptic ulceration, abdominal pain, and nausea may occur.
(d) Hypotension may occur.
(e) Thrombocytopenia may occur.
(4) Clinical use
(a) Tolazoline is used primarily as a pulmonary vasodilator in neonates with persistent pulmonary hypertension.
(b) Tolazoline dose: Bolus 0.5 to 2 mg/kg; infusion 0.5 to 10 mg/kg/h.
3. Angiotensin converting enzyme (ACE) inhibitors
a. Benazepril (Lotensin)
(1) An oral ACE inhibitor used primarily to treat hypertension; it is largely similar to captopril (see Section b: Captopril). Benazepril must first be converted to an active metabolite in the liver.
(2) Benazepril dose: 10 to 40 mg PO in 1 or 2 daily doses.
b. Captopril (Capoten)
(a) In common with all ACE inhibitors, captopril blocks the conversion of angiotensin I (inactive) to angiotensin II in the lung. This decrease in plasma angiotensin II levels causes vasodilation, generally without reflex increases in HR or CO.
(b) Many tissues contain ACE (including heart, blood vessels, and kidney), and inhibition of the local production of angiotensin II may be important in the mechanism of action of ACE inhibitors.
(c) Plasma and tissue concentrations of kinins (e.g., bradykinin) and prostaglandins increase with ACE inhibition and may be responsible for some side effects.
(d) Captopril, enalaprilat, and lisinopril inhibit ACE directly, but benazepril, enalapril, fosinopril, quinapril, and ramipril are inactive “prodrugs” and must undergo hepatic metabolism into the active metabolites.
(2) Offset occurs primarily by renal elimination with a half-life of 1.5 to 2 h. Dosages of all ACE inhibitors (except fosinopril) should be reduced with renal dysfunction.
(3) Advantages (in common with all ACE inhibitors)
(a) Oral vasodilator with efficacy in chronic hypertension
(b) No tachyphylaxis or reflex hemodynamic changes
(c) Improved symptoms and prolonged survival in CHF, hypertension, and after MI
(d) May retard progression of renal disease in diabetics
(e) Antagonizes LV remodeling after myocardial infarction
(4) Disadvantages (in common with all ACE inhibitors)
(a) Reversibly decreased renal function, due to reduced renal perfusion pressure. Patients with renal artery stenosis bilaterally (or in a single functioning kidney) are at particular risk of renal failure.
(b) Increased plasma K+ and hyperkalemia may occur, due to reduced aldosterone secretion.
(c) Not all angiotensin arises through the ACE pathway (“angiotensin escape”).
(d) ACE inhibition also leads to accumulation of bradykinin (which may underlie side effects of ACE inhibitors).
(e) Allergic phenomena (including angioedema and hematologic disorders) occur rarely. Captopril may induce severe dermatologic reactions.
(f) Many patients develop a chronic nonproductive cough.
(g) Chronic use of ACE inhibitors (and ARBs) appears associated with exaggerated hypotension with induction of general anesthesia.
(h) Severe fetal abnormalities and oligohydramnios may occur during second- and third-trimester exposure.
(c) Myocardial infarction (secondary prevention)
(d) For all indications, outcome benefits appear to be a drug class effect; any ACE inhibitor will provide them.
(e) Prevention of renal insufficiency (in the absence of renal artery stenosis), especially in at-risk population (diabetics)
(6) Administration. PO
(7) Clinical use
(a) Captopril dose
(i) Adults: 12.5 to 150 mg PO in 2 or 3 daily doses, with the lower doses being used for treatment of heart failure
(ii) Infants: 50 to 500 μg/kg daily in three doses
(iii) Children older than 6 mos: 0.5 to 2 mg/kg/day divided into three doses
(b) Interactions. ACE inhibitors interact with digoxin (reduced digoxin clearance) and with lithium (Li intoxication). May predispose to exaggerated hypotension with anesthesia. Captopril interacts with allopurinol (hypersensitivity reactions), cimetidine (CNS changes), and insulin or oral hypoglycemic drugs (hypoglycemia).
c. Enalapril (Vasotec)
(1) Actions. An oral ACE inhibitor used to treat hypertension and CHF, enalapril is very similar to captopril (see Section b). The drug must first be converted to an active metabolite in the liver.
(2) Clinical use. Enalapril dose: 2.5 to 40 mg/day PO in one or two divided doses.
d. Enalaprilat (Vasotec-IV)
(1) Actions. Enalaprilat is an IV ACE inhibitor that is the active metabolite of enalapril. It is used primarily to treat severe or acute hypertension and is very similar to captopril (see Section b).
(2) Offset is by renal elimination, with a half-life of 11 h.
(a) This drug has a longer duration of action than nitrates, thereby avoiding the need for continuous infusion. It can help extend BP control into the postoperative period.
(b) Unlike hydralazine, reflex increases in HR, CO, and MVO2 are absent.
(a) There is a longer onset time (15 min) than with IV nitroprusside. Peak action may not occur until 1 to 4 h after the initial dose.
(b) Pregnancy. Oligohydramnios and fetal abnormalities may be induced. Use during pregnancy should be limited to life-threatening maternal conditions.
(5) Enalaprilat IV dose
(a) Adults: 1.25 mg IV slowly every 6 h (maximum 5 mg IV every 6 h). In renal insufficiency (creatinine clearance less than 30 mL/min), initial dose is 0.625 mg, which may be repeated after 1 h; then 1.25 mg.
(b) Pediatrics: A dosage of 250 μg/kg IV every 6 h has been reported to be effective in neonates with renovascular hypertension.
e. Fosinopril (monopril)
(1) An oral ACE inhibitor most often used for hypertension, fosinopril is very similar to captopril (see Section b). The drug must first be converted to an active metabolite in the gastrointestinal tract and liver.
(2) Unlike other ACE inhibitors, substantial biliary excretion occurs, so that doses do not need to be altered with renal insufficiency.
(3) Fosinopril dose: 10 to 80 mg PO in 1 or 2 daily dose.
f. Lisinopril (prinivil, zestril)
(1) Lisinopril is an oral ACE inhibitor most often used for hypertension. It is very similar to captopril (see Section b). The drug must first be converted to an active metabolite in the liver.
(2) Lisinopril dose: 5.40 mg PO once daily.
g. Quinapril (accupril)
(1) An oral ACE inhibitor used primarily to treat hypertension, quinapril is very similar to captopril (see Section b). The drug must first be converted to an active metabolite in the liver.
(2) Quinapril dose: 5 to 80 mg PO daily in one or two divided doses.
h. Ramipril (altace)
(1) An oral ACE inhibitor used primarily to treat hypertension, ramipril is very similar to captopril (see Section b). The drug must first be converted to an active metabolite in the liver.
(2) Ramipril dose: 1.25 to 10 mg PO once daily.
i. Aceon (perindopril)
(1) An oral ACE inhibitor used primarily to treat hypertension or HF-LV dysfunction after MI. It is very similar to captopril (see Section b). This prodrug must be hydrolyzed to an active metabolite in the liver.
(2) Perindopril dose: 2 to 8 mg daily (most often given as a single dose).
j. Mavik (trandolopril)
(1) An oral ACE inhibitor used primarily to treat hypertension or HF-LV dysfunction after MI. It is very similar to captopril (see Section b). This prodrug must be hydrolyzed to an active metabolite in the liver.
(2) Trandolopril dose: 1 to 8 mg daily in patients not already receiving a diuretic. Usual starting dose is 1 mg daily (2 mg daily for control of hypertension in blacks).
k. Univasc (moexipril)
(1) An oral ACE inhibitor used primarily to treat hypertension or HF-LV dysfunction after MI. It is very similar to captopril (see Section b.). This prodrug must be hydrolyzed to an active metabolite in the liver.
(2) Moexipril dose: 7.5 mg to 30 mg daily (most often as a single dose).
4. Angiotensin receptor blockers (ARBs)
(1) Plasma concentrations of angiotensin II and aldosterone may increase despite treatment with ACE inhibitors because of accumulation of angiotensin or because of production catalyzed via non-ACE–dependent pathways (e.g., chymase).
(2) Selective Angiotensin type-1 receptor (AT1) blockers prevent angiotensin II from directly causing the following:
(b) Sodium retention
(c) Release of NE
(d) LV hypertrophy and fibrosis
(3) Angiotensin type-2 receptors (AT-2) are not blocked: Their actions including NO release and vasodilation remain intact.
(1) Oral vasodilator
(2) No tachyphylaxis or reflex hemodynamic changes
(3) ARBs have minimal interaction with CYP system, so few drug interactions.
(4) Improved symptoms and survival in CHF, hypertension, and after MI
(5) Stroke prevention in hypertension and LV dysfunction
(6) May retard progression of renal disease (particularly in diabetics)
(7) Antagonizes LV remodeling after myocardial infarction
(8) Lacks common side effects of ACE inhibitors (cough, angioedema)
(1) There is the potential for decreased renal function, due to reduced renal perfusion pressure. Patients with renal artery stenosis bilaterally (or in a single functioning kidney) are at particular risk.
(2) Increased plasma K+ and hyperkalemia may occur, especially when clinicians fail to recognize the consequences of reduced aldosterone secretion.
(1) Intolerance of ACE inhibitors—outcome benefits of ACE inhibitors appear to be largely shared by ARBs
(4) Prevention of renal insufficiency (in the absence of renal artery stenosis) in at-risk population (diabetics)
(5) Data are inconclusive as to whether there is an outcome benefit to adding ARBs to an ACE inhibitor.
e. Specific agents
(1) Losartan (Cozaar)
(a) Both drug and first metabolite antagonize angiotensin
(b) Requires dosage adjustment in both renal and hepatic disease
(c) Peak concentration about 1 h after oral administration
(d) Dosing 25–100 mg/day in 1 or 2 daily doses
(e) Takes 4 to 6 wks to see peak effect
(2) Irbesartan (Avapro)
(a) Once-daily dosing
(b) Primarily hepatic metabolism
(c) Usual dose 150–300 mg daily in 1 dose
(3) Candesartan (Atacand)
(a) Taken as a prodrug (candesartan cilexetil is hydrolyzed to candesartan during absorption from GI tract)
(b) Only ARB that is totally dependent on metabolism for clinical effect
(c) Prodrug is not detectable in blood after oral dosing (assumed to be completely metabolized to candesartan).
(d) Usual dose 8–32 mg once daily
(e) Most of the drug is eliminated unchanged in urine (30%) and feces (70%, 25% of this as inactive metabolite).
(f) Dose adjustment required with renal disease; no adjustment required in mild to moderate hepatic disease
(4) Eprosartan (Teveten)
(a) Approximately two-thirds of oral dose eliminated unchanged in bile; remainder eliminated unchanged in urine
(b) Usual dose 400–800 mg in 1 or 2 daily)
(c) Peak blood concentration 1 to 3 h after oral dose
(d) Most of the drug eliminated unchanged in feces with remainder eliminated unchanged in urine (small fraction of conjugated drug)
(e) No need to routinely adjust dosage in patients with mild to moderate renal or hepatic disease
(5) Telmisartan (Micardis)
(a) Typical dose 40 to 80 mg/day in 1 daily dose
(b) No dosage adjustment required for renal disease; manufacturer urges “caution” in hepatic disease.
(c) Steady-state concentrations were achieved after 5 to 7 days of dosing.
(d) Almost all of the administered drug is eliminated unchanged in bile.
(6) Valsartan (Diovan)
(a) Typical dose 80 mg to 320 mg in 1 daily dose
(b) Extensively studied in both hypertension and heart failure
(c) Maximum concentration reached within 3 h of oral dosing
(d) Most of the administered drug eliminated unchanged in bile
(e) Should be given 40 mg twice daily in heart failure; once-daily dosing is approved in hypertension.
(7) Olmesartan (Benicar)
(a) Omesartan medoxomil is a prodrug (de-esterified in GI tract much like candesartan)
(b) Peak blood concentrations after oral dosing within 3 h
(c) 60% administered dose eliminated unchanged in bile, remainder eliminated unchanged in urine
(d) Once-daily dosing in hypertension
(e) Usual doses 20 to 40 mg daily
(f) No dosage adjustment recommended in patients with mild to moderate renal or hepatic disease
5. Direct renin inhibitor. Aliskiren is the single member of this class. It is used for treatment of hypertension and has the same side effects and contraindications as the ARBs. It is dosed at 150–300 mg in a single daily dose.
6. Central α2 agonists
a. Clonidine (Catapres)
(a) Clonidine reduces sympathetic outflow by activating central α2 receptors thereby reducing NE release by peripheral sympathetic nerve terminals.
(b) Clonidine is a partial agonist (activates receptor submaximally but also antagonizes effects of other α2 agonists).
(c) There is some direct vasoconstrictor action at α2-receptors on vascular smooth muscle, but this effect is outweighed by the vasodilation induced by these receptors.
(d) Has “local anesthetic” effect on peripheral nerve and produces analgesia by actions on spinal cord when administered via epidural or caudal route
(e) Has been added to intermediate-duration local anesthetics (e.g., mepivacaine) to nearly double the duration of analgesia after peripheral nerve blocks
(a) Long duration (β half-life; 12 h)
(b) Peak effect 1.5 to 2 h after an oral dose
(a) α2 Agonists potentiate general anesthetics and narcotics through a central mechanism. This effect can reduce substantially doses of anesthetics and narcotics required during anesthesia.
(b) There are no reflex increases in HR or contractility.
(c) Clonidine reduces sympathetic coronary artery tone.
(d) It attenuates hemodynamic responses to stress.
(e) Prolongs duration of regional anesthesia
(a) Rebound hypertension prominent after abrupt withdrawal
(b) Clonidine may potentiate opiate drug effects on CNS.
(c) Sedation is dose-dependent.
(5) Clinical use
(a) Clonidine dose
(i) Adult: 0.2 to 0.8 mg PO daily (maximum 2.4 mg/day). When used as anesthetic premedication, the usual dose is 5 μg/kg PO.
(ii) Pediatrics: 3 to 5 μg/kg every 6 to 8 h.
(b) Rebound hypertension frequently follows abrupt withdrawal. Clonidine should be continued until immediately before the operation, and either it should be resumed soon postoperatively (by transdermal skin patch, nasogastric tube, or PO) or another type of antihypertensive drug should be substituted. Alternatively, clonidine can be replaced by another drug 1 to 2 wks preoperatively.
(c) Intraoperative hypotension may occur.
(d) Transdermal clonidine patches require 2 to 3 days to achieve therapeutic plasma drug levels.
(e) Guanabenz and guanfacine are related drugs with similar effects and hazards.
(f) Use of clonidine may improve hemodynamic stability during major cardiovascular surgery.
(g) Clonidine attenuates sympathetic responses during withdrawal from alcohol or opioids in addicts.
(h) It may reduce postoperative shivering.
(i) It may be added to intermediate-duration local anesthetic solutions prior to peripheral nerve blocks to prolong the duration of action.
b. Guanabenz (Wytensin)
(1) Oral α2 agonist is similar to clonidine.
(2) Guanabenz dose: 4 mg PO bid (maximum 32 mg PO bid).
c. Guanfacine (Tenex)
(1) Oral α2 agonist is similar to clonidine.
(2) Actions. Guanfacine has a longer duration of action than clonidine due to renal elimination (half-life: 15 to 20 h).
(3) Guanfacine dose: 1 mg PO daily (maximum 3 mg daily).
7. Other vasodilators
(a) Fenoldopam is a short-acting DA-1 receptor agonist which causes peripheral vasodilation. The mechanism appears to be through stimulation of cAMP.
(b) Unlike dopamine, fenoldopam has no α- or β-adrenergic receptor activity at clinical doses and thus no direct actions on HR or cardiac contractility.
(c) Fenoldopam stimulates diuresis and natriuresis.
(a) Relative to other short-acting IV vasodilators, fenoldopam has almost no systemic toxic effects.
(b) Fenoldopam alone among vasodilators stimulates diuresis and natriuresis comparable to “renal dose” (0.5 to 2 μg/kg/min) dopamine.
(c) Fenoldopam, unlike dopamine, reduces global and regional cerebral blood flow.
(a) As is true for other dopaminergic agonists, fenoldopam may induce nausea in awake patients.
(4) Clinical use
(a) Fenoldopam is an appropriate single agent to use whenever a combination of a vasodilator and “renal dose” dopamine is employed; for example, for hypertensive patients recovering after CPB.
(b) Fenoldopam carries no risk of cyanide or of methemoglobinemia and may have theoretical advantages over both nitroprusside and nitroglycerin for control of acute hypertension.
(c) For treatment of urgent or emergent hypertension in adults we initiate fenoldopam at 0.05 μg/kg/min and double the dose at 5- to 10-min intervals until it achieves BP control. Doses of up to 1 μg/kg/min may be required.
(d) The limited data available in pediatrics suggest that weight-adjusted doses at least as great as those used in adults are necessary.
(e) For inducing diuresis and natriuresis, we have found that doses of 0.05 μg/kg/min are effective in adults.
b. Alprostadil (Prostaglandin1, PGE1, Prostin VR)
(1) Actions. This drug is a direct vasodilator acting through specific prostaglandin receptors on vascular smooth-muscle cells.
(2) Offset occurs by rapid metabolism by enzymes located in most body tissues, especially the lung.
(a) Alprostadil selectively dilates the ductus arteriosus (DA) in neonates and infants. It may maintain patency of an open DA for as long as 60 days of age and may open a closed DA for as long as 10 to 14 days of age.
(b) Metabolism by lung endothelium reduces systemic vasodilation compared with its potent pulmonary vascular dilating effect.
(a) Systemic vasodilation and hypotension
(b) May produce apnea in infants (10% to 12%), especially if birth weight is less than 2 kg. Fever and seizures are also possible.
(c) Expensive agent
(d) Reversible platelet inhibition
(5) Administration. Infused IV or through umbilical arterial catheter
(6) Indications for use
(a) Cyanotic congenital heart disease with reduced pulmonary blood flow
(b) Severe pulmonary hypertension with right heart failure
(7) Clinical use
(a) Alprostadil dose: Usual IV infusion starting dose is 0.05 μg/kg/min. The dose should be titrated up or down to the lowest effective value. Doses as great as 0.4 μg/kg/min may be required.
(b) Intravenous alprostadil is sometimes used in combination with left atrial NE infusion for treatment of severe pulmonary hypertension with right heart failure.
c. Epoprostenol (PGI2) is used for the long-term treatment of primary pulmonary hypertension and pulmonary hypertension associated with scleroderma. The acute treatment of pulmonary hypertension and RV failure is summarized in Table 2.2.
IX. Calcium channel blockers [3,5]
A. General considerations
1. Tissues utilizing calcium. Calcium is required for cardiac contraction and conduction, smooth-muscle contraction, synaptic transmission, and hormone secretion.
2. How calcium enters cells. Calcium ions (Ca2+) reach intracellular sites of action in two ways, by entering the cell from outside or by being released from intracellular storage sites. These two mechanisms are related because Ca2+ crossing the sarcolemma acts as a trigger (Ca-induced Ca release), releasing sequestered Ca2+ from the sarcoplasmic reticulum into the cytoplasm. These processes can raise intracellular free Ca2+ concentrations 100-fold.
3. Myocardial effects of calcium. The force of myocardial contraction relates to the free ionized calcium concentration in cytoplasm. Increased [Ca2+] causes contraction and decreased [Ca2+] permits relaxation. At the end of systole, energy-consuming pumps transfer Ca2+ from the cytoplasm back into the sarcoplasmic reticulum, decreasing free cytoplasmic [Ca2+]. If ischemia prevents sequestration of cytoplasmic Ca2+, diastolic relaxation of myocardium is incomplete. This abnormal diastolic stiffness of the heart raises LVEDP.
4. Myocardial effects of CCBs. CCBs owe much of their usefulness to their ability to reduce the entry of the “trigger” current of Ca2+. This reduces the amount of Ca2+ released from intracellular stores with each heartbeat. Therefore, all CCBs in large enough doses reduce the force of cardiac contraction, although this effect often is counterbalanced by reflex actions in patients. Clinical dosages of some CCBs, such as nifedipine and nicardipine, do not produce myocardial depression in humans.
5. Vascular smooth muscle and the cardiac conduction system are particularly sensitive to Ca2+ channel blockade. All CCBs cause vasodilation.
6. Site selectivity. CCBs affect certain tissues more than others. Thus, verapamil in clinical dosages depresses cardiac conduction, whereas nifedipine does not.
7. Direct versus indirect effects. Selection of a particular CCB is based primarily on its relative potency for direct cellular effects in the target organ versus its relative potency for inducing cardiovascular reflexes.
B. Clinical effects common to all CCBs
1. Peripheral vasodilation
a. Arterial vasodilation reduces LV afterload, and this helps offset any direct negative cardiac inotropic action.
b. Venous effects. Preload usually changes little because venodilation is minimal, and negative inotropy often is offset by reduced afterload. However, if CCBs reduce myocardial ischemia and diastolic stiffness, filling pressures may decrease.
c. Regional effects. Most vascular beds are dilated, including the cerebral, hepatic, pulmonary, splanchnic, and musculoskeletal beds. Renal blood flow autoregulation is abolished by nifedipine, making it pressure-dependent.
d. Coronary vasodilation is induced by all CCBs. These drugs are all highly effective for coronary vasospasm.
e. CCBs versus nitrates
(1) Unlike nitrates, CCBs do not incite tachyphylaxis.
(2) Unlike nitrates, several CCBs are associated with increased bleeding.
f. Reversal of vasodilation. α Agonists such as phenylephrine often restore BP during CCB-induced hypotension, but usual doses of calcium salts are often ineffective.
2. Depression of myocardial contractility. The degree of myocardial depression that occurs following administration of a CCB is highly variable, depending on the following factors:
a. Selectivity. The relative potency of the drug for myocardial depression compared with its other actions is an important factor. Nifedipine and other dihydropyridines are much more potent as vasodilators than as myocardial depressants; clinical dosages that cause profound vasodilation have minimal direct myocardial effects. Conversely, vasodilating dosages of verapamil may be associated with significant myocardial depression in some patients.
b. Health of the heart. A failing ventricle will respond to afterload reduction with improved ejection. An ischemic ventricle will pump more effectively if ischemia is reversed. As CCBs reduce afterload and ischemia, CO may rise with CCB therapy in certain situations. Direct negative inotropic effects may not be apparent.
c. Sympathetic reflexes can counteract direct myocardial depression and vasodilation due to CCBs.
d. Reversal of myocardial depression. Calcium salts, β agonists, and PDE inotropes all can be used to help reverse excessive negative inotropy and heart block. Electrical pacing may be needed.
3. Improving myocardial ischemia
a. CCBs may improve oxygen supply by the following actions:
(1) Reversing coronary artery spasm
(2) Vasodilating the coronary artery, increasing flow to both normal and poststenotic regions. Diltiazem and verapamil appear to preserve coronary autoregulation, but nifedipine may cause a coronary steal.
(3) Increasing flow through coronary collateral channels
(4) Decreasing HR (prolonging diastolic duration during which subendocardium is perfused) with verapamil and diltiazem
b. CCBs may improve oxygen consumption by
(1) Diminishing contractility
(2) Decreasing peak LV wall stress (afterload reduction)
(3) Decreasing HR (by verapamil and diltiazem)
4. Electrophysiologic depression
a. Spectrum of impairment of AV conduction
(1) Verapamil. Clinical doses usually produce significant electrophysiologic effects. Thus, verapamil has a high relative potency for prolonging AV refractoriness compared with its vasodilating potency.
(2) Dihydropyridines. On the other hand, nifedipine and other drugs of this class in dosages that produce profound vasodilation have no effect on AV conduction.
(3) Diltiazem is intermediate between nifedipine and verapamil.
b. AV node effects. The depression of AV nodal conduction by CCBs may be beneficial for its antiarrhythmic effect.
c. Sinoatrial (SA) node effects. Diltiazem and verapamil decrease sinus rate, whereas nifedipine and nicardipine often increase HR slightly.
d. Ventricular ectopy due to mitral valve prolapse, atrial or AV nodal disease, and some forms of digitalis toxicity may respond to CCBs.
5. Clinical uses
a. Myocardial ischemia mainly for symptom reduction; note that outcome benefit is not well established for CCBs.
b. Hypertension (outcome benefits are better established for thiazide diuretics and ACE inhibitors; short-acting CCBs have been associated with worsened outcomes)
c. Hypertrophic cardiomyopathy by relieving LV outflow obstruction
d. Cerebral vasospasm following subarachnoid hemorrhage (nimodipine)
e. Possible reduction of cyclosporine nephrotoxicity with concomitant CCB therapy in transplant recipients. Also, CCBs may potentiate the immunosuppressive action of cyclosporine.
f. Migraine prophylaxis
C. Specific agents
1. Amlodipine (Norvasc)
a. Actions. A dihydropyridine CCB with actions closely resembling those of nifedipine (see Section 7), amlodipine is primarily a vasodilator without important negative cardiac inotropy. It is used most commonly for oral treatment of hypertension.
b. Amlodipine dose: 2.5 to 10 mg PO once daily; decrease with hepatic dysfunction
2. Bepridil (Vascor)
a. Actions. In addition to inhibiting Ca channels, bepridil also inhibits voltage-gated Na channels, prolongs cardiac repolarization, and causes additional negative cardiac inotropy by a non-calcium channel mechanism. Its vasodilator actions are selective for the coronary circulation; nevertheless, hypotension may be induced.
b. Offset is by hepatic metabolism (with active metabolites). The elimination half-life is 33 h.
(1) Oral treatment of angina pectoris that is not controlled by other medical therapies
(2) Does not cause clinical myocardial depression but not recommended for use with severe LV dysfunction
(1) Proarrhythmic action. Bepridil can increase QT intervals, which may cause ventricular arrhythmias; Torsades de Pointes occurs rarely. For this reason, bepridil is contraindicated in patients with a prolonged QT interval, conduction abnormalities, or elevated K+.
(2) T-wave abnormalities may be induced.
e. Bepridil dose: 200 to 400 mg PO once daily
3. Diltiazem (Cardizem)
a. Diltiazem is a benzothiazepine calcium blocker.
b. Actions. Diltiazem has a selective coronary vasodilating action, causing a greater increase in coronary flow than in other vascular beds.
c. Offset occurs by hepatic metabolism (60%) and renal excretion (35%). Plasma elimination half-life is 3 to 5 h. The active metabolite is desacetyldiltiazem.
(1) Diltiazem often decreases HR of patients in sinus rhythm.
(2) It is effective in treating and preventing symptoms of classic or vasospastic myocardial ischemia. Diltiazem does not improve outcome in these conditions.
(3) Used for rate control of SVT (see Section VIII.E).
(4) Perioperative hypertension can be controlled with IV diltiazem.
(1) Sinus bradycardia and conduction system depression are possible.
(2) No evidence for outcome benefit in hypertension or CAD relative to other agents
(1) Myocardial ischemia, both classic angina and coronary artery spasm
(3) Supraventricular tachycardia, including atrial fibrillation or flutter (see Section VIII.E).
(4) Sinus tachycardia, especially intraoperative or postoperative
g. Diltiazem dose (adult) (see Section VIII.E)
4. Felodipine (Plendil)
a. Actions. A dihydropyridine CCB with actions closely resembling those of nifedipine (see Section 7). Felodipine is primarily a vasodilator without clinically important negative cardiac inotropy. It is used most commonly for oral treatment of hypertension.
b. Felodipine dose: 2.5 to 10 mg PO once daily.
5. Isradipine (DynaCirc)
a. Actions. A dihydropyridine CCB with actions closely resembling those of nifedipine (see Section 7), isradipine is primarily a vasodilator without clinically important negative cardiac inotropy. It is used most commonly for oral treatment of hypertension.
b. Isradipine dose: 5 to 10 mg PO in 2 daily doses
6. Nicardipine (Cardene)
a. Actions. A dihydropyridine calcium blocker with actions closely resembling those of nifedipine (see Section 7), nicardipine is primarily a vasodilator without clinically important negative cardiac inotropy. It is used most commonly for treatment of hypertension.
b. IV nicardipine
(1) The IV preparation is a highly effective vasodilator that is widely used in surgical patients, causing only minimal HR increase and no increase in ICP. Nicardipine lacks the rebound hypertension that can follow nitroprusside withdrawal. Nicardipine causes less venodilation than nitroglycerin.
(2) Offset. Metabolism occurs in the liver, with plasma α and β half-lives of 3 and 14 min, respectively. When IV administration is stopped, 50% offset vasodilation occurs in approximately 30 min.
(3) Clinical use. Nicardipine IV is effective for control of perioperative hypertension; it also improves diastolic LV function during ischemia by acceleration of myocardial relaxation (lusitropy). Nicardipine can elevate plasma cyclosporine levels.
c. Nicardipine dose: PO: 60–120 mg in 3 daily doses; IV: 1 to 4 μg/kg/min in adults, titrated to BP. The drug causes phlebitis when infused for more than 12 h through a peripheral IV catheter.
7. Nifedipine (Adalat, Procardia)
a. Nifedipine is a dihydropyridine calcium channel blocker.
c. Offset occurs by hepatic metabolism. Plasma elimination half-life is 1.5 to 5 h, and there are no active metabolites.
(1) Profound vasodilation is the predominant effect.
(a) Coronary vasodilation and relief of coronary vasospasm reduce myocardial ischemia.
(b) Peripheral vasodilation can improve CO via LV unloading.
(2) Virtually no myocardial depression occurs in clinical dosages. Therefore, nifedipine can be used in patients with poor ventricular function.
(3) Generally this drug is devoid of conducting system toxicity.
(4) It may be combined with β-blockers without increased risk of AV block, or with nitrates provided that the patient is monitored for excessive vasodilation.
(1) It is extremely light-sensitive; thus, no IV preparation is available.
(2) Administration must be PO or via mucosa of the nose or mouth.
(3) Severe hypotension is possible due to peripheral vasodilation.
(4) No significant antiarrhythmic effect occurs unless relief of myocardial ischemia decreases ischemia-induced arrhythmias.
(5) Peripheral edema is possible (not due to heart failure).
(6) The drug must be avoided in hypertrophic cardiomyopathy due to increased aortic outflow tract obstruction.
(7) Short-acting versions of this drug have been associated with worsened outcome when used for chronic treatment of essential hypertension.
f. Clinical use
(1) Nifedipine dose: PO, 10 to 40 mg tid; sublingual, 10 to 20 mg liquid (extracted from capsule). In hypertension, use extended-release formation at 30–90 mg in 1 daily dose
(2) Nifedipine generally is selected for its vasodilator and antianginal properties.
(3) The sublingual (or intranasal) route is useful in treatment of hypertensive emergencies when no IV is present.
(4) If excessive vasodilation with hypotension occurs, phenylephrine may be used (high dosages may be required).
(5) In rare patients, angina is exacerbated with nifedipine. This may be related to hypotension or to a coronary steal phenomenon.
8. Nimodipine (Nimotop)
a. Actions. A dihydropyridine CCB with actions closely resembling those of nifedipine (see Section I), nimodipine lacks clinically important negative cardiac inotropy. It is a more effective dilator of cerebral arteries compared with other CCBs. Its primary use is in patients with subarachnoid hemorrhage for oral treatment and prophylaxis of cerebral vasospasm and neurologic deficits.
b. Nimodipine dose: 60 mg PO (or by nasogastric tube) every 4 h.
9. Verapamil (Calan, Isoptin) (see Section VIII.E).
10. Flunarizine (a vasodilating CCB indicated for prophylaxis against migraine headaches in countries other than the United States, where it has not received regulatory approval)
X. Pharmacologic control of HR and rhythm
A. Overview of arrhythmias [5,22,23]
1. Conduction pathway. Drug effects on the cardiac rhythm depend upon the anatomy and physiology of the cardiac conduction pathway. The cardiac impulse normally arises in the SA node and passes through the atria to enter the AV node. Impulses then transit the conduction system (including the His bundle, the major bundle branches, and the Purkinje fiber network) before spreading into the ventricular myocardium. Agents that inhibit conduction from the sinus node to (or through) the AV node prolong the interval from the P wave (which represents atrial systole) to the QRS complex (which represents ventricular systole), manifest as the “PR” interval on the ECG (Fig. 2.1). Conversely, agents that prolong conduction through the specialized conduction system or the ventricle lengthen the QRS complex.
2. The role of the conduction system in arrhythmias. Drugs that suppress AV nodal conduction (β-blockers, calcium channel blockers, adenosine) terminate SVTs that originate in the AV node, or involve the AV node in a re-entrant pathway (Table 2.4). Conversely, rhythms that originate in atrial tissue above the AV node, including atrial flutter or fibrillation, as well as paroxysmal rhythms stimulated by catecholamines (common in perioperative patients), respond to AV nodal blockade with slowing of the ventricular response rate, since the passage of impulses from the atrium to the ventricle through the AV node is slowed. Junctional tachycardias, common in surgical patients, arise in the conduction system, and may convert to sinus rhythm in response to AV nodal blockers only if they originate very close to the AV node, but are otherwise unresponsive to drugs acting on the AV node. Ventricular arrhythmias usually exhibit no beneficial response to AV nodal blockade, since these rhythms originate in tissues distal to the AV node.
3. Initiating the cardiac action potential (AP). The effects of drugs on the surface ECG can be predicted from their effects on the ion channel currents that compose the cardiac AP (Fig. 2.2). The cardiac AP represents the time-varying transmembrane potential of the cardiac myocyte before, during, and after a depolarization. The AP is divided into five distinct phases; the channels responsible for “Phase 0” initiate the AP and underlie impulse propagation. In the atria and the ventricles, the phase 0 current is generated by sodium channels, and is inhibited by the local anesthetic-type drugs (lidocaine, procainamide, etc.) that prolong the QRS complex. In AV and SA nodal cells (not shown in Fig. 2.2), phase 0 is produced by L-type calcium channels, so drugs that suppress calcium channels (β-blockers and calcium channel blockers) slow the HR by acting on the SA node, and prolong the PR interval by slowing conduction through the AV node. The latter effect renders the AV node a more efficient “filter” for preventing rapid trains of atrial beats from passing into the ventricle, and hence the rationale for AV nodal blockade during SVT.
Table 2.4 The response of common supraventricular tachyarrhythmias to IV adenosine
4. The later phases of the AP [17–19] reflect repolarization, and are modulated by a number of outward (mainly potassium) and inward (mainly calcium) currents. In general, the long plateau (phase 2) is maintained by L-type calcium current, and is terminated (phase 3) by potassium currents (Fig. 2.2) and inactivation of the calcium currents. Hence, the QT interval on the ECG reflects the length of the AP, and is determined by a delicate balance between these currents. Drugs that reduce or shorten calcium current tend to abbreviate the AP plateau, shorten the QT, and reduce the inward movement of calcium ions into the cardiac cell (hence, the negative inotropic effect). Conversely, agents that block outward potassium current prolong the AP and the QT interval on the ECG. An example is shown in Figure 2.2.
5. Re-entry underlies a wide variety of supraventricular and ventricular arrhythmias, and implies the existence of a pathological circus movement of electrical impulses around an anatomic loop (accessory pathway or infarct scar) or a “functional” loop (ischemia or drug-induced dispersion of AP duration). Fibrillation, in either the atrium or ventricle, is believed to involve multiple coexistent re-entrant circuits of the functional type. Drugs may terminate re-entry through at least two mechanisms. Agents that suppress currents responsible for initiation of the AP, the Na current in ventricle (Fig. 2.2) or the calcium current in the AV node, may slow or block conduction in a re-entrant pathway, and thus terminate an arrhythmia. Interventions that prolong the AP, such as potassium channel blockade (Fig. 2.2), in turn prolong the refractory period of cells in a re-entrant circuit, and thus “block” impulse propagation through the circuit. Agents operating through the latter mechanism are more effective in suppressing fibrillation in the atrium and ventricle.
6. Triggered automaticity may occur during phase 2 or 3 (early afterdepolarization, or “EAD”) or phase 4 (delayed afterdepolarization, or “DAD”). Drugs that block potassium channels prolong the duration of the AP, lengthening the QT interval on the ECG (Fig. 2.2), and thereby stimulate EADs. In addition, low serum potassium, hypomagnesemia, and slow HR synergistically prolong the QT and precipitate EADs. EADs in turn elicit a polymorphic VT known as Torsades de Pointes. At the same time, inherited mutations that suppress potassium channel function provoke the congenital long QT syndrome, an inherited condition where the QT interval is prolonged and the risk for Torsades de Pointes is increased. Moreover, “silent” mutations in potassium channels may provoke QT prolongation and torsades only during exposure to potassium-channel–blocking drugs; hence, the “acquired” and congenital long QT syndromes are mechanistically related and represent distinct points on a continuum of ion channel dysfunction. Drugs commonly used in the perioperative period that may prolong the QT and provoke torsades are listed in Table 2.5. More comprehensive listings are available on-line (see, for example, http://www.arizonacert.org/medical-pros/drug-lists/drug-lists.htm).
DADs are most common during conditions of intracellular calcium ion (Ca2+) overload. Common clinical entities are digitalis toxicity, excess catecholamine states (exercise, acute myocardial infarction, perioperative stress), and heart failure. Arrhythmias provoked by DADs are responsive to maneuvers aimed at lowering intracellular Ca2+, such as calcium channel blockade.
Figure 2.2 Relationship between the ECG (top), the AP in the ventricle (second panel), and individual ion currents. The amplitudes of the currents are not on the same scales. The solid lines represent the baseline; the dotted lines the computation when IKr is reduced by 50%. Note that this change not only prolongs the action potential duration (APD) (as expected), but also generates changes in the time course of ICa-L, IKs, and the sodium–calcium exchange current, each of which thus also modulates the effect of reduced IKr on the APD. (From Roden DM, Balser JR, George AL Jr, et al. Cardiac ion channels. Annu Rev Physiol. 2002;64:431–475, with permission. 2002 by Annual Reviews www.annualreviews.org.)
B. Nonsustained ventricular tachycardia (NSVT) [5,17,22]
1. Definition and etiology. NSVT is three or more premature ventricular contractions (PVCs) occurring at a rate exceeding 100 beats/min, and lasting 30 s or less without hemodynamic compromise. These arrhythmias occur up to 50% of patients during or after thoracic and major vascular surgeries, often in the absence of cardiac disease.
Table 2.5 QT-prolonging drugs (partial listing emphasizing agents used perioperatively)
2. Management. The rhythms do not influence early or late mortality in patients with preserved LV function, and do not require suppressive drug therapy in most circumstances. However, NSVT with normal LV function may be the first sign of a reversible, life-threatening condition, such as hypoxemia or cardiac ischemia, and therefore should always trigger a thorough evaluation. Among patients with low CO following CABG (requiring pressor support), NSVT is an independent predictor of more serious, life-threatening arrhythmias. Similarly, patients who undergo aortic valve replacement and have NSVT are at increased risk for sustained ventricular arrhythmias. There are no studies available to guide therapy in these circumstances, so clinical management is empiric. Hemodynamically unstable patients with marginal perfusion may deteriorate with recurrent episodes of NSVT (problematic ventricular pacing or intra-aortic balloon counterpulsation) and may benefit from suppression with IV amiodarone, lidocaine, or βblockade if hemodynamically tolerated. Repletion of postbypass hypomagnesemia (2 g MgCl2 IV) reduces the incidence of NSVT after cardiac surgery.
C. Sustained ventricular arrhythmias [5,17,22]
1. Monomorphic VT. The mechanism for monomorphic VT is a re-entrant pathway around scar tissue from a healed myocardial infarction, producing a constant QRS morphology. Patients may have a stable (perfusing) BP with this rhythm, and procainamide or amiodarone are often preferred over lidocaine for chemical cardioversion. In cases of hemodynamic instability, DC countershocks should be utilized for cardioversion and antiarrhythmic drug therapy considered as a means to maintain sinus rhythm. Monomorphic VT is less common during surgery than the polymorphic VTs (discussed later).
2. Long QT polymorphic VT (Torsades de Pointes). As discussed earlier, this rhythm is usually an acquired complication of therapy with drugs that prolong the QT interval (Table 2.5). The management of Torsades is distinctive. Following DC countershocks to achieve conversion, additional maneuvers are aimed at shortening the QT interval in order to maintain sinus rhythm. This includes IV magnesium sulfate and maneuvers to increase the HR (atropine, isoproterenol, or ventricular pacing). Antiarrhythmic drug therapy is considered when the rhythm is refractory to these measures, and agents producing minimal potassium channel blockade, such as lidocaine or phenytoin, should be chosen to avoid further prolongation of the QT interval. Among the antiarrhythmic agents that prolong the QT interval, the incidence of Torsades de Pointes is lowest with amiodarone; hence, IV amiodarone is a rational alternative therapy for polymorphic VT of unclear etiology that is refractory to other therapies.
3. Normal QT polymorphic VT and VF are the most common, life-threatening ventricular arrhythmias in perioperative patients, and may occur in patients with ischemic or structural heart disease. IV antiarrhythmic agents are common adjuncts to DC countershocks, and the agents recommended include procainamide and amiodarone. There are no prospective clinical data evaluating the efficacy of antiarrhythmic agents during cardiac arrest in perioperative patients, but in blinded, randomized, prospective trials, IV amiodarone is superior to placebo or lidocaine in producing a short-term survival benefit when treating out-of-hospital cardiac arrest refractory to DC cardioversion . There are no convincing human clinical trials to support lidocaine as an effective therapy for treating shock-resistant VT/VF, and the agent now carries an “indeterminate” recommendation in published guidelines. Bretylium was removed from the ACLS treatment guidelines because of a high occurrence of side effects (postganglionic adrenergic blockade, orthostatic hypotension with continuous infusion), limited availability from the manufacturer, and the availability of safer agents. In all cases, defibrillation is the means to achieve conversion to sinus rhythm, and these antiarrhythmic agents should be viewed as supplements to help maintain sinus rhythm.
4. Specific agents available in IV form [5,17,22]
a. Procainamide (Pronestyl, Procan-SR)
(a) Loading dose
(i) IV: 10 to 50 mg/min (or 100 mg every 2 to 5 min) up to 17 mg/kg.
(ii) Pediatric IV: 3 to 6 mg/kg given slowly.
(b) Maintenance dose
(i) Adult: IV infusion, 2 mg/kg/h; PO, 250 to 1,000 mg every 3 h
(ii) Children: IV infusion, 20 to 50 μg/kg/min; PO, 30 to 50 mg/kg/day divided into four to six doses.
Therapeutic plasma level is usually 4 to 10 μg/mL. With bolus administration, the duration of action is 2 to 4 h. Metabolism is both hepatic (50%, N-acetylprocainamide) and renal. Slow acetylators are more dependent on renal elimination. Patients with reduced renal function require lower maintenance doses, and need close monitoring of serum levels and the ECG QT intervals.
(3) Adverse effects
(a) High serum levels or rapid loading may cause negative inotropic and chronotropic effects, leading to hypotension and hypoperfusion. Overdose may require pacing and/or β-agonist therapy.
(b) High serum levels of procainamide and/or its principal active metabolite (N-acetylprocainamide) induce QT prolongation and Torsades de Pointes. Discontinuation of therapy should be considered if the corrected QT interval exceeds 450 ms.
(c) CNS excitability may occur with confusion and seizures.
(d) A lupus-like syndrome may be seen with long-term therapy.
b. Amiodarone (Cordarone)
(a) PO: 800 to 1,600 mg/day for 1 to 3 wks, gradually reducing dosage to 400 to 600 mg/day for maintenance.
(i) Loading: For patients in a perfusing rhythm, 150 mg over 10 min in repeated boluses until sustained periods of sinus rhythm occur. For patients in pulseless VT/VF, more rapid bolus administration may be warranted. Patients often require 2 to 4 or more boluses for a sustained response.
(ii) Maintenance: 1 mg/min for 6 h, then 0.5 mg/min thereafter, with the goal of providing approximately 1 g/day.
(2) Pharmacokinetics. The drug is metabolized hepatically, but has very high lipid solubility that results in marked tissue accumulation. The elimination half-life is 20 to 100 days. Hence, for patients treated chronically, it is usually unnecessary to “reload” amiodarone when doses are missed during surgery, and postoperatively patients usually resume their preoperative dosing.
(3) Adverse effects
(a) Amiodarone is an α- and β-receptor noncompetitive antagonist, and therefore has potent vasodilating effects, and can render negative inotropic effects. Hence, vasoconstrictors, IV fluid, and occasionally β agonists are required for hemodynamic support, especially during the IV amiodarone loading phase.
(b) Amiodarone blocks potassium channels and typically prolongs the QT interval, but is only rarely associated with Torsades de Pointes. The risk of torsades on amiodarone therapy is poorly correlated with the QT interval, and QT prolongation on amiodarone, if not excessive, does not usually require cessation of therapy.
(c) Amiodarone use may cause sinus bradycardia or heart block due to β-receptor blockade, and patients requiring sustained IV amiodarone therapy sometimes require pacing or low doses of supplemental β agonists.
(d) The side effects of long-term oral dosing (subacute pulmonary fibrosis, hepatitis, cirrhosis, photosensitivity, corneal microdeposits, hypothyroidism, or hyperthyroidism) are of little concern during short-term (days) IV therapy.
(e) This drug may increase the effect of oral anticoagulants, phenytoin, digoxin, diltiazem, quinidine, and other drugs.
c. Lidocaine (lignocaine, Xylocaine)
(a) Loading dose: 1 mg/kg IV, a second dose may be given 10 to 30 min after first dose. Loading dose is sometimes doubled for patients on CPB who are experiencing VF prior to separation. The total dose should not exceed 3 mg/kg.
(b) Maintenance dose: 15 to 50 μg/kg/min (i.e., 1 to 4 mg/min in adults).
(2) Pharmacokinetics. Duration of action is 15 to 30 min after administration of a bolus dose. Metabolism is hepatic, and 95% of metabolites are inactive. However, for infusions lasting more than 24 h, serum levels should be monitored. Many factors that reduce hepatic metabolism will increase serum levels, including CHF, α agonists, liver disease, and advanced age.
(3) Adverse effects
(a) CNS excitation may result from mild to moderate overdose, producing confusion or seizures. At higher doses, CNS depression will ensue, producing sedation and respiratory depression. At still higher doses lidocaine will produce severe myocardial depression.
(b) Lidocaine, like other antiarrhythmics with sodium-channel–blocking properties (amiodarone, procainamide), slows ventricular excitation. Hence, patients with AV nodal block who are dependent upon an idioventricular rhythm may become asystolic during lidocaine therapy.
D. Bradyarrhythmias [5,17,22]
a. CPR with cardiac compressions should be instituted immediately. As hypoxemia is a common cause of asystole, efforts to secure the airway and provide oxygenation may be critical resuscitation measures.
b. The ECG recording of VF is sometimes “fine” (low-amplitude), and may be confused with asystole. If VF cannot be excluded, DC countershocks should be applied.
c. Definitive therapy consists of ventricular pacing and/or transcutaneous pacing if immediately available (see Chapter 15).
d. For pharmacologic therapy, useful drugs include atropine (1 mg IV, repeat every 3 to 5 min) and epinephrine (1 mg IV push, repeat every 3 to 5 min). Isoproterenol infusion may be a poor choice for asystole because of reduced coronary perfusion pressure during CPR.
2. HR below 40 bpm
a. Cardiac compressions may induce VF, so if possible, pharmacologic agents or pacing should be utilized to increase the HR.
b. Certain persons (i.e., trained athletes) may tolerate HRs near 40 bpm. Patients with reduced diastolic compliance (aortic stenosis, hypertensive cardiomyopathy, ongoing ischemia, etc.) cannot increase SV in response to bradycardia, and poorly tolerate extreme bradycardia.
c. For pharmacologic therapy, useful drugs include atropine, isoproterenol, and epinephrine. Avoid antiarrhythmics such as lidocaine, procainamide, bretylium, or amiodarone because these agents may slow a ventricular escape rhythm, worsening the bradycardia.
3. Drug therapies for bradyarrhythmias [5,17,22]
(1) Dosing. IV bolus: In adults, use 0.4 to 1 mg (may repeat); in children, use 0.02 mg/kg (minimum 0.1 mg, maximum 0.4 mg, may repeat).
(2) Pharmacokinetics. The HR effects of IV atropine appear within seconds, and effects last as long as 15 to 30 min; when given IM, SC, or PO, offset occurs in approximately 4 h. There is minimal metabolism of the drug, and 77% to 94% of it undergoes renal elimination.
(3) Adverse effects. Atropine is a competitive antagonist at muscarinic cholinergic receptors, and its adverse effects are largely systemic manifestations of this receptor activity.
(a) Tachycardia (undesirable with coronary disease)
(b) Exacerbation of bradycardia by low dosages (0.2 mg or less in an adult)
(c) Sedation (especially in pediatric and elderly patients)
(d) Urinary retention
(e) Increased intraocular pressure in patients with closed-angle glaucoma. Atropine may be safely given, however, if miotic eye drops are given concurrently.
(1) Dosing (adults). 0.1 mg IV, repeated at 2- to 3-min intervals
(2) Differences from atropine. Less likely to cause sedation, but also less likely to produce tachycardia and less likely to be effective for treatment of critical bradycardia. This agent may be chosen to manage mild intraoperative bradycardia, or as an antagonist to the HR slowing effects of neostigmine when reversing neuromuscular blockade. Atropine remains the drug of choice in severe or life-threatening sinus bradycardia.
c. Isoproterenol (Isuprel)
(1) General features. Isoproterenol is a synthetic catecholamine with direct β1- and β2-agonist effects, and thus has both positive inotropic (through β1-mediated enhanced contractility plus β2-mediated vasodilation) and positive chronotropic effects. Isoproterenol is the drug of choice for drug treatment of bradycardia with complete heart block.
(2) Dosing. IV infusion is 0.02 to 0.50 μg/kg/min.
(3) Pharmacokinetics. The agent is used as a continuous infusion, and has a short half-life (2 min) making it titratable. It is partly metabolized in the liver (MAO, COMT) and partly excreted unchanged (60%).
(4) Adverse effects
(a) The major potential adverse effect of isoproterenol is myocardial ischemia in patients with CAD, because the combination of tachycardia, positive inotropy, and hypotension may create a myocardial oxygen supply–demand mismatch.
(b) The agent may provoke supraventricular arrhythmias, or may unmask pre-excitation in patients with an accessory AV conduction pathway (e.g., WPW syndrome).
E. Supraventricular arrhythmias [5,17,22,23]
1. Therapy-based classification
a. General. SVT often foreshadows life-threatening conditions that may be correctable in the surgical patient. Hence, the initial management of the hemodynamically stable surgical patient who suddenly develops SVT should not be on heart-directed pharmacologic therapies, but rather on potential correctable etiologies that may include hypoxemia (O2 saturation), hypoventilation (end tidal CO2), hypotension (absolute or relative hypovolemia due to bleeding, anaphylaxis, etc.), light anesthesia, electrolyte abnormalities (K+ or Mg2+), or cardiac ischemia (HR, nitroglycerine).
b. Hemodynamically unstable patients. Patients with low BP (e.g., systolic BP less than 80 mm Hg), cardiac ischemia, or other evidence of end-organ hypoperfusion require immediate synchronous DC cardioversion. While some patients may only respond transiently to cardioversion in this setting (or not at all), a brief period of sinus rhythm may provide valuable time for correcting the reversible causes of SVT (see earlier) and/or instituting pharmacologic therapies (see later). During cardiac or thoracic surgery, patients may experience SVT during dissection of the pericardium, placement of atrial sutures, or insertion of the venous cannulae required for CPB. If hemodynamically unstable SVT occurs during open thoracotomy, the surgeon should attempt open synchronous cardioversion. Patients with critical coronary lesions or severe aortic stenosis with SVT may be refractory to cardioversion, and thus enter a malignant cascade of ischemia and worsening arrhythmias that requires the institution of CPB. Hence, early preparation for CPB is recommended before inducing anesthesia in those cardiac surgery patients judged to be at exceptionally high risk for SVT and consequent hemodynamic deterioration.
c. Hemodynamically stable patients
(1) Adenosine therapy (Table 2.4)
(a) In certain patients the SVT involves a re-entrant pathway involving the AV node. These rhythms typically have a regular R–R interval, and are common in relatively healthy patients. Adenosine administered as a 6 mg IV bolus (repeated with 12 mg if no response) may terminate the SVT.
(b) Many of the rhythms commonly seen in the perioperative period do not involve the AV node in a re-entrant pathway, and AV nodal block by adenosine in such cases will produce only transient slowing of the ventricular rate. This may lead to “rebound” speeding of the tachycardia following the adenosine effect. Adenosine should be avoided in cases where the rhythm is recognizable and known to be refractory to adenosine (atrial fibrillation, atrial flutter). The hallmark of atrial fibrillation is an irregularly irregular R–R interval.
(c) Junctional tachycardias are common during the surgical period (particularly after surgery for congenital heart disease in children), and sometimes convert to sinus rhythm in response to adenosine, depending on the proximity of the site of origin to the AV node. Ventricular arrhythmias exhibit no response to adenosine since these rhythms originate.
(2) Rate control therapy
(a) Rationale for rate control. In most cases, ventricular rate control is the mainstay of therapy.
(i) Lengthening diastole serves to enhance LV filling, thus enhancing SV.
(ii) Slowing the ventricular rate reduces MVO2 and lowers the risk of cardiac ischemia.
(b) Rationale for drug selection. The most common selections are IV β-blockers or calcium channel blockers because of their rapid onset.
(i) Among the IV β-blockers, esmolol has the shortest duration of action, rendering it titratable on a minute-to-minute basis, and allowing meaningful dose adjustments during periods of surgery that provoke changes in hemodynamic status (i.e., bleeding, abdominal traction). The drug has obligatory negative inotropic effects that are problematic for patients with severe LV dysfunction.
(ii) Both IV verapamil and IV diltiazem are calcium channel blockers that are less titratable than esmolol, but nonetheless rapidly slow the ventricular rate in SVT. Moreover, IV diltiazem has less negative inotropic action than verapamil or esmolol and is therefore preferable in patients with heart failure.
(iii) IV digoxin slows the ventricular response during SVT through its vagotonic effects at the AV node, but should be temporally supplemented with other IV agents because of its slow onset (approximately 6 h).
(c) Accessory pathway rhythms. AV nodal blockade can reduce the ventricular rate in WPW, and improve hemodynamic status. However, 10% to 35% of patients with WPW eventually develop atrial fibrillation. In this case, the rapid rate of atrial excitation (greater than 300 impulses/min), normally transmitted to the ventricle after “filtering” by the AV node, is instead be transmitted to the ventricle via the accessory bundle at a rapid rate. The danger of inducing VT/VF in this scenario is exacerbated by treatment with classic AV nodal blocking agents (digoxin, calcium channel blockers, β-blockers, and adenosine) because they reduce the accessory bundle refractory period. Hence, WPW patients who experience atrial fibrillation should not receive AV nodal blockers. IV procainamide slows conduction over the accessory bundle, and is an option for treating AF in patients with accessory pathways.
d. Specific rate control agents [5,17,22,23]
(please also see the earlier section on β-blockers)
(a) Dosing. During surgery and anesthesia, the standard 0.25 to 0.5 mg/kg load (package insert) may be accompanied by marked hypotension. In practice, reduced IV bolus doses of 12.5 to 25 mg are titrated to effect, followed by an infusion of 50 to 200 μg/kg/min. Transient hypotension during the loading phase may usually be managed with IV fluid or vasoconstrictors (phenylephrine).
(b) Pharmacokinetics. Esmolol is rapidly eliminated by a red blood cell esterase. After discontinuation of esmolol, most drug effects are eliminated within 5 min. The duration of esmolol action is not affected when plasma pseudocholinesterase is inhibited by echothiophate or physostigmine.
(c) Adverse effects
(i) Esmolol is a potent, selective β1-receptor antagonist, and may cause hypotension through both vasodilation and negative inotropic effects.
(ii) Compared to nonselective β-blockers, esmolol is less likely to elicit bronchospasm, but should still be used with caution in patients with known bronchospastic disease.
(i) IV load (adults): 5 to 15 mg, consider administering in 1- to 2 mg increments during surgery and anesthesia, or in unstable patients. Dose may be repeated after 30 min.
(ii) Maintenance IV: 5 to 15 mg/h.
(iii) PO (adults): 40 to 80 mg tid to qid (maximum 480 mg/day).
(iv) Pediatric dose: 75 to 200 μg/kg IV; may be repeated.
(b) Pharmacokinetics. Elimination occurs by hepatic metabolism, and plasma half-life is 3 to 10 h, so lengthy intervals (hours) between dose increments for IV infusions should be utilized to avoid cumulative effects.
(c) Adverse effects
(i) Verapamil blocks L-type calcium channels and may cause hypotension because of both peripheral vasodilation and negative inotropic effects, especially during the IV loading phase. The vasodilatory effects may be mitigated by administration of IV fluid or vasoconstrictors (i.e., phenylephrine). Patients with severe LV dysfunction may not tolerate IV verapamil, and may be better candidates for IV diltiazem (see later).
(ii) Verapamil (given chronically) reduces digoxin elimination and can raise digoxin levels, producing toxicity.
(a) Dosing (adult)
(i) IV loading: 20 mg IV over 2 min. May repeat after 15 min with 25 mg IV if HR exceeds 110 bpm. Smaller doses or longer loading periods may be used in patients who have myocardial ischemia, hemodynamic instability, or who are anesthetized.
(ii) Maintenance: Infusion at 5 to 15 mg/h, depending on HR control.
(iii) PO dose: 120 to 360 mg/day (sustained-release preparations are available).
(b) Pharmacokinetics. Metabolism is both hepatic (60%) and renal excretion (35%). Plasma elimination half-life is 3 to 5 h, so lengthy intervals (hours) between dose increases for IV infusions should be utilized to avoid cumulative effects.
(c) Adverse effects
(i) Diltiazem, like all calcium channel blockers, elicits vasodilation and may evoke hypotension. At the same time, partly due to its afterload reducing properties, IV diltiazem is less likely to compromise CO in patients with reduced LV function (relative to other AV nodal blockers) and is the drug of choice for rate control in this circumstance.
(ii) Sinus bradycardia is possible, so diltiazem should be used with caution in patients with sinus node dysfunction or those also receiving digoxin or β-blockers.
(4) High-dose IV magnesium sulfate
(a) Dosing. Regimens including a 2 to 2.5 g initial bolus, followed by a 1.75 g/h infusion, are described.
(b) Issues with use. High-dose magnesium is used rarely for SVT, but may nonetheless successfully provide rate control for patients with SVT. In some cases, rates of conversion to sinus rhythm exceeding placebo or antiarrhythmic agents have been noted. The use of these high magnesium doses requires close monitoring of serum levels, and should be avoided in patients with renal insufficiency.An increased requirement for temporary pacing due to the AV nodal blockade has also been noted. Magnesium potentiates neuromuscular blockers; thus, this agent can cause life-threatening hypoventilation in spontaneously breathing patients who have residual blood levels of these agents.
e. Cardioversion of SVT
(1) Limitations of pharmacologic or “chemical” cardioversion
(a) The 24-h rate of spontaneous conversion to sinus rhythm for recent-onset perioperative SVT exceeds 50%, and many patients who develop SVT under anesthesia will remit spontaneously within hours of emergence.
(b) Most of the antiarrhythmic agents with activity against atrial arrhythmias have limited efficacy when utilized in IV form for rapid chemical conversion. Although 50% to 80% efficacy rates are cited for many IV antiarrhythmics in uncontrolled studies, these findings are an artifact of high placebo rates of conversion (approximately 60% over 24 h). Although improved rates of chemical cardioversion are seen with high doses of IV amiodarone (approximately 2 g/day), the potential for undesirable side effects in the perioperative setting requires further study.
(c) Most agents have adverse effects, including negative inotropic effects or vasodilation (amiodarone, procainamide). In addition, these agents may provoke polymorphic ventricular arrhythmias (Torsades de Pointes). While less common with amiodarone, newer IV agents that exhibit high efficacy for converting atrial fibrillation (i.e., ibutilide) exhibit rates of torsades as high as 8%.
(2) Rationale for cardioversion. In the operating room, chemical cardioversion should be aimed mainly at patients who cannot tolerate (or do no respond to) IV rate control therapy, or who fail DC cardioversion and remain hemodynamically unstable. Intraoperative elective DC cardioversion in an otherwise stable patient with SVT also carries inherent risks (VF, asystole, and stroke). Moreover, the underlying factors provoking SVT during or shortly after surgery are likely to persist beyond the time of cardioversion, inviting recurrence. Hence, when elective DC cardioversion is considered, it may be prudent to first establish a therapeutic level of an antiarrhythmic agent that maintains sinus rhythm (i.e., procainamide, amiodarone), with a view to preventing SVT recurrence following electrical cardioversion. Guidelines for administration of IV procainamide and amiodarone are provided in an earlier section of this chapter (see Section VIII, C4).
f. SVT prophylaxis for postoperative patients [17,25]
SVT may occur during the days following surgery, and occurs within the first 4 postoperative days in up to 40% of cardiac surgeries. Many postoperative prophylaxis regimens have been evaluated, and are discussed in recent reviews. Prophylactic administration of a number of drugs typically used to slow AV nodal conduction (particularly β-blockers and amiodarone) may reduce the incidence of postoperative atrial fibrillation (particularly after cardiothoracic surgery), but by no means eliminate the problem. Nonetheless, antiarrhythmic prophylaxis should be considered in selected patients at high risk for hemodynamic or ischemic complications from postoperative SVT.
XI. Diuretics [26,35]
A. Actions. Most IV diuretics act at the loop of Henle in the kidney to block resorption of electrolytes from the tubule. Loop diuretics block the sodium-potassium-chloride transporter. Thiazide diuretics block the electroneutral sodium-chloride transporter. Amiloride and triamterene block apical (non–voltage-gated) sodium channels. Spironolactone binds and inhibits the mineralocorticoid receptor. This action increases excretion of water and electrolytes (Na, Cl, K, Ca, and Mg) from the body.
B. Adverse effects
1. Effect shared by all diuretics
a. Cross-sensitivity with sulfonamides (except ethacrynic acid)
2. Effects shared by thiazides and loop diuretics
a. Skin reactions
b. Interstitial nephritis
d. Hypomagnesemia (effects of thiazides and loop diuretics are diminished by potassium-sparing diuretics such as spironolactone or triameterene)
e. Risk of hyponatremia greater with thiazides than with loop diuretics
3. Effects specific to loop diuretics
a. Increased serum uric acid
b. Ototoxicity. Deafness, usually temporary, may occur with large drug doses or coadministration with an aminoglycoside antibiotic. One possible mechanism for this is drug-induced changes in endolymph electrolyte composition.
4. Effects of thiazide diuretics
c. Mild metabolic alkalosis (“contraction” alkalosis)
d. Hyperglycemia, glucose intolerance
f. Rare pancreatitits
5. Effects of potassium-sparing diuretics
a. Hyperkalemia (sometimes with metabolic acidosis)
b. Gynecomastia (with increased doses of spironolactone)
c. Amiloride excreted by kidneys, so duration prolonged in renal failure
C. Specific drugs
1. Loop diuretics
a. Furosemide (Lasix)
(1) Pharmacokinetics. Renal tubular secretion of unchanged drug and of glucuronide metabolite. Half-life of 1.5 h
(2) Clinical use
(i) Adults: The usual oral dosing is 20–320 mg in 2 daily dose. The usual IV starting dose for patients not currently receiving diuretics is 2.5 to 5 mg, increasing as necessary to a 200 mg bolus. Patients already receiving diuretics usually require 20 to 40 mg initial doses to produce a diuresis. A continuous infusion (0.5 to 1 mg/kg/h) at approximately 0.05 mg/kg/h in adults produces a more sustained diuresis with a lower total daily dose compared with intermittent bolus dosing. Patients resistant to loop diuretics (e.g., after long-term dosing in hepatic failure) may benefit from combinations of furosemide and thiazide diuretics.
(ii) Pediatric: 1 mg/kg (maximum, 6 mg/kg). The pediatric infusion rate is 0.2 to 0.4 mg/kg/h.
(b) Because furosemide is a sulfonamide, allergic reactions may occur in sulfonamide-sensitive patients (rare).
(c) Furosemide often causes transient vasodilation of veins and arterioles, with reduced cardiac preload.
b. Bumetanide (Bumex)
(1) Pharmacokinetics. Combined renal and hepatic elimination. Half-life is 1 to 1.5 h.
(2) Clinical use
(a) Dosing: The usual oral dosing is 25–100 mg in 2 or 3 daily doses. 0.5 to 1 mg IV, may be repeated every 2 to 3 h to a maximum dose of 10 mg/day.
(b) Myalgias may occur.
c. Ethacrynic acid (Edecrin)
(1) Pharmacokinetics. Combined renal and hepatic elimination
(2) Clinical use
(a) Dosing: 50 mg IV (adult dose) or 0.5 to 1 mg/kg (maximum 100 mg) titrated to effect
(b) Usually is reserved for patients who fail to respond to furosemide or bumetanide, or who are allergic to sulfonamides (thiazides and furosemide are chemically related to sulfonamides)
2. Thiazide diuretics
a. Mechanism/pharmacokinetics. The mechanism of the antihypertensive effect of thiazide diuretics remains the subject of debate. All thiazides increase the urinary excretion of sodium and chloride, acting on the sodium-chloride symporter in the distal renal tubules.
b. Clinical use and dosing (Table 2.6)
3. Potassium-sparing diuretics
a. Amiloride (Midamor)
Amiloride works by inhibiting sodium channels in renal epithelium of the late distal tubule and collecting duct. This mildly increases the excretion of sodium and chloride. Amiloride decreases the lumen-negative voltage across the membrane, decreasing the excretion of K+, H+, Ca2+, and Mg2+. Amiloride has 15% to 25% oral bioavailability. It has a roughly 21-h half-life and is predominantly eliminated by the renal excretion of the intact drug.
(2) Clinical use
Amiloride is a weak diuretic, so it is almost never used as a sole agent, but most commonly in combination with other, stronger diuretics (such as thiazides or loop diuretics) to augment their diuretic and antihypertensive effects and reduce the risk of hypokalemia.
(a) Dosing: Usual dose is 5–10 mg/day in 1 or 2 doses added to a loop or thiazide diuretic. Doses more than 10 mg/day have rarely been given.
Table 2.6 Thiazides and related diuretics: dosages
(b) This agent is also available as a combination product with hydrochlorothiazide (Moduretic).
b. Eplerenone (Inspra)
This agent has the same mechanism of action as spironolactone and it is used for the same indications. It is an effective antihypertensive. It has been shown to prolong life in patients with LV dysfunction following myocardial infarction.
(2) Dosing: The drug is initiated at 25 mg/day and may be increased to 100 mg/day as tolerated by the patient.
c. Spironolactone (Aldactone)
Spironolactone is a competitive antagonist to the mineralocorticoid receptor found in the cytoplasm of epithelial cells in the late distal tubule and collecting duct. Thus, it opposes the actions of endogenous aldosterone. After binding the receptor, the aldosterone–receptor complex migrates to the cell nucleus, regulating production of a series of “aldosterone-induced proteins.” The AIPs ultimately increase transepithelial sodium-chloride transport, and the lumen-negative transepithelial membrane potential, increasing the secretion of K+ and H+ into the tubular lumen. Spironolactone antagonizes these effects. Spironolactone has also been shown to inhibit the cardiac remodeling process and to prolong life in patients with chronic HF. The side effects of spironolactone include hyperkalemia and gynecomastia. Spironolactone has about a 65% oral bioavailability and a very short half-life. It has active metabolites with prolonged (16-h half-life) actions.
(2) Clinical use
Spironolactone is a weak diuretic, so it is almost never used as a sole agent, but most commonly in combination with other, stronger diuretics (such as thiazides or loop diuretics) to augment their diuretic and antihypertensive effects and reduce the risk of hypokalemia. Spironolactone prolongs life in patients with heart failure and is now part of standard therapy for symptomatic patients with this condition.
(a) Dosing: The usual dose is 12.5 to 25 mg/day, but this may be increased as needed up to 100 mg/day in 1 or 2 daily doses. This agent is also available as a combination product with hydrochlorothiazide (Aldactazide).
This agent is believed to have the same mechanism of action as amiloride and it is used for the same indications as amiloride. It is approximately one-tenth as potent as amiloride. Triamterene has 50% oral bioavailability and a half-life of roughly 4.5 h. It is eliminated through hepatic biotransformation to an active metabolite that is excreted in the urine.
(2) This agent is usually given in doses of 50 to 150 mg/day in one or two doses in combination with thiazide or loop diuretics. It is also found in a combination product with hydrochlorothiazide (Dyazide).
4. Osmotic diuretics
(1) Mechanism/pharmacokinetics. Mannitol is an osmotic diuretic that is eliminated unchanged in urine. It is also a free-radical scavenger.
(2) Clinical use
(a) Unlike the loop diuretics (e.g., furosemide), mannitol retains its efficacy even during low glomerular filtration states (e.g., shock).
(b) Diuresis with this agent may have protective effects in some clinical scenarios (i.e., CPB, poor renal perfusion, hemoglobinuria, or nephrotoxins), possibly related to free-radical scavenging.
(c) As an osmotically active agent in the bloodstream, it is sometimes used to reduce cerebral edema and ICP. Mannitol is administered routinely (as prophylaxis) by many clinicians during anesthesia for patients with intracranial mass lesions.
(3) Dosing: Initial dose is 12.5 g IV to a maximum of 0.5 g/kg.
(4) Adverse effects
(a) It may produce hypotension if administered as a rapid IV bolus.
(b) It may induce transient pulmonary edema as intravascular volume expands before diuresis begins.
The current version of this chapter is based on the one in the previous edition, and the author acknowledges with thanks the important contributions of the coauthors of that previous version: Drs Jeffrey Balser and David Larach.
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