Factors affecting blood pressure

Typical measurement of blood pressure is relative to a recurring cardiac cycle of atrial and ventricular contractions and relaxations (Figure 21-1). The cycle is divided into the systolic phase and the diastolic phase. The systolic phase is the portion in which ventricular contraction occurs, resulting in ejection of blood through the aorta. Conversely, diastole is the period of ventricular relaxation and blood filling. Systolic blood pressure (SBP) is the peak pressure reached during ventricular ejection, and diastolic blood pressure (DBP) is the lowest pressure reached right before ventricular ejection. Arterial pressure is typically recorded as SBP/DBP, for example, 120/80 mm Hg. Mean arterial pressure (MAP) refers to the pressure that drives blood into the tissues averaged over the entire cardiac cycle. Because the cardiac cycle is pulsatile rather than continuous and because two-thirds of the normal cardiac cycle is spent in diastole, MAP is not the arithmetic mean of the SBP and DBP. MAP is defined as the product of cardiac output (CO) and systemic vascular resistance (SVR), as follows:

< ?xml:namespace prefix = "mml" />[2(DBP) + SBP]/3 or MAP = CO × SVR

Systemic vascular resistance is used to define the resistance to flow of the vasculature that must be overcome to push blood through the peripheral circulation. Cardiac output is the amount of blood that is ejected into the aorta and travels through the systemic circulation per unit of time. Cardiac output is dependent on the sum of all local blood flow regulations and is shown in the following equation as the product of heart rate (HR) and stroke volume (SV). Stroke volume is the amount of blood ejected from the heart during systole. Changes in any of these components may alter the effects of the others.

CO = HR × SV

Summing up all components that affect the MAP, the following equation may better illustrate how these components relate to blood pressure:

MAP = HR × SV × SVR

The use of therapies such as fluids, vasopressors, and inotropes to maintain cardiovascular stability is directed toward altering each of these components, as seen in Table 21-2. The various vasopressors currently on the market have different affinities for the various receptors located within the body and exert different effects on the hemodynamic parameters, as seen in Table 21-3. Vasopressors and inotropes are not always first-line therapy; on the contrary, fluids are the mainstays for improving hypotensive episodes. Vasopressors and inotropes have considerable side effects, and certain medications interact with various vasopressors and inotropes, leading to alterations in hemodynamic parameters as seen in Table 21-4.

In addition to vascular tone, another component that may affect changes in tissue perfusion is vascular volume. Intravascular volume depletion may influence stroke volume and affect MAP as well. This component may be indirectly measured as the pulmonary capillary wedge pressure (PCWP), central venous pressure, or preload. In other words, using a device called a pulmonary artery catheter, a measurement of the amount of fluid returning to the heart can be used to estimate the PCWP. With this measurement, the clinician can evaluate a patient-specific response to fluid therapy and vasoactive therapy. The use of a pulmonary artery catheter is associated with complications such as infection, pneumothorax, bleeding, or thrombus formation.

Catecholamines

Norepinephrine (levophed) and epinephrine (adrenalin chloride)

Norepinephrine (Levophed) and epinephrine (Adrenalin Chloride) are endogenous catecholamines that are secreted by the adrenal medulla. Epinephrine is ultimately synthesized by the catalytic actions of tyrosine hydroxylase, which converts the amino acid tyrosine to levodopa and subsequently to dopamine, norepinephrine, and epinephrine.^1,2 These neurotransmitters travel to sympathetic nerve endings, where they are released to stimulate other nerve fibers and to stimulate an excitatory response. Norepinephrine and epinephrine stimulate α receptors on the vasculature and β receptors, also located within the vasculature as well as in the myocardium. α receptors within the vasculature cause vasoconstriction, whereas β receptors cause vasodilation. Most vascular beds within the body contain β receptors; however, they are outnumbered by α receptors, so any epinephrine and norepinephrine stimulation of β receptors is negligible or of no effect, yielding a net response of vasoconstriction. In addition, β receptors more densely populate the myocardium compared with α receptors, leading to a net effect of tachycardia.^3,4

Isoproterenol (isuprel)

Isoproterenol (Isuprel) is a synthetic catecholamine used for the treatment of symptomatic bradycardia or torsades de pointes. Isoproterenol works solely as an agonist of β receptors. By stimulating β₁-adrenergic receptors, it exerts pronounced inotropic and chronotropic effects. By stimulating β₂-adrenergic receptors, it leads to smooth muscle relaxation of the bronchi, skeletal muscle, vasculature, and gastrointestinal tract. Venous return to the heart is also increased by vasodilation of the venous bed. The use of isoproterenol is limited because of its pronounced stimulatory effect on the heart rate.⁴

Dopamine

Dopamine (DA) is an endogenous catecholamine that is a precursor to norepinephrine. The usual vasopressor dose of dopamine is 5 to 20 μg/kg/min; dopamine directly stimulates β receptors, producing chronotropic and inotropic effects and leading to increased cardiac output, and stimulates peripheral α receptors, causing increased systemic vascular resistance.

Previously, low-dose DA (1 to 5 μg/kg/min) was thought to stimulate selectively the DA₁ and DA₂ receptors in the splanchnic and renal artery beds, causing vasodilation and increased blood flow. This belief has been nullified, and use of low-dose DA is considered an antiquated form of practice. It has been suggested that improvement of renal and splanchnic blood flow as a result of DA stems from its benefits on cardiac output. Cardiac output enhances perfusion to all major organs, including blood flow to the kidney.

There is a higher likelihood of adverse effects occurring with higher doses of dopamine when used in patients with cardiac failure because of the increase in afterload and myocardial oxygen demand. Adverse effects include tachyarrhythmias, ectopic beat, palpitations, and decreased perfusion.

Phenylephrine

In contrast to epinephrine, phenylephrine is purely an α agonist, yet it differs from epinephrine only in that it lacks a hydroxyl group (−OH) on the benzene ring. Phenylephrine induces vasoconstriction in most vascular beds, elevating SBP and DBP. Phenylephrine exerts an effect on systemic blood pressure by elevating total peripheral resistance; the direct vasoconstriction of the aortic vasculature imposes a reflex bradycardia on the heart. No significant adverse respiratory effects are noted with phenylephrine therapy.

Vasopressin

Aside from the pressor effects of vasopressin (which are discussed subsequently in the section on advanced cardiac life support), vasopressin may be used in the setting of septic shock, not only because of its pressor effect, but also because of its water-retentive effects. Vasopressin is a naturally occurring hormone also known as antidiuretic hormone. Vasopressin shows affinity for V₁ and V₂ receptors located in the collecting ducts in the kidneys, which contribute to water conservation and concentration of urine. The use of vasopressin may be especially beneficial in the setting of sepsis because vasopressin is deficient in septic patients. The dose of vasopressin in the setting of septic shock is initiated at a rate of 0.04 U/min and titrated to a dose of 0.01 U/min.

The 2008 practice guidelines⁵ published by the Society of Critical Care Medicine do not recommend vasopressin as the initial vasopressor of choice or as a lone agent. Precaution stems from the fact that vasopressin infusion may decrease splanchnic blood flow. Other settings in which vasopressin may be used include diabetes insipidus at doses of 5 to 10 U given intramuscularly or subcutaneously and repeated two or three times per day. Vasopressin has also been used to treat esophageal bleeding at doses up to 2 U/min. Caution is also needed when treating conditions other than shock; myocardial ischemia may ensue as a result of the potent vasoconstrictive properties at higher doses.

Inotropic agents

Dobutamine

Dobutamine is indicated for the short-term treatment of decompensated heart failure secondary to depressed contractility. Dobutamine is a synthetic catecholamine that is chemically related to dopamine; however, in contrast to dopamine, it is not metabolized to norepinephrine, and it does not stimulate dopamine receptors.⁴ Its pharmacologic actions are due to the effects of its racemic components. The (R)-isomer is responsible for its activity on the β₁ and β₂ receptors, causing predominant positive inotropic and chronotropic effects and vasodilatory effects, respectively. This combination of effects enhances cardiac output and stroke volume. The (S)-isomer is responsible for its activity on the α₁ receptors, causing vasoconstriction.^1,6 The vasodilatory β₂-adrenergic effects counterbalance the vasoconstrictive α₁ effects, leading to minor changes in systemic vascular resistance usually seen at lower doses. With increasing doses, the β₂-vasodilatory actions predominate over the α₁-vasoconstrictive effect, causing a decrease in systemic and pulmonary vascular resistance. The decline in systemic and pulmonary vascular resistance may also be secondary to enhanced cardiac output.

As an inotropic agent, dobutamine has adverse cardiac effects, which include arrhythmias, increase in myocardial oxygen consumption and demand, tachycardia, and hypotension. A limiting factor when dobutamine is used for more than 72 hours is tachyphylaxis; this may be due to a downregulation of β₁ receptors and may be overcome by increasing the dose. In patients with sulfite sensitivity, allergic reactions such as anaphylaxis or life-threatening asthmatic episodes may occur because dobutamine formulations contain sulfites.⁴

Phosphodiesterase inhibitors: inamrinone and milrinone

Phosphodiesterase inhibitors (also known as inodilators), such as inamrinone (formerly known as amrinone) and milrinone, are both inotropic and vasodilator agents by increasing myocardial contractility and inducing vascular smooth muscle relaxation. These effects are mitigated by inhibition of intracellular phosphodiesterase (subclass III). Phosphodiesterase is an enzyme responsible for the breakdown of cyclic adenosine 3′,5′-monophosphate (cAMP). An increase in cAMP concentration mediates an increase in intracellular ionized calcium, which is responsible for its inotropic effect, and cAMP-dependent protein phosphorylation, causing relaxation of vascular muscle. Hemodynamically, phosphodiesterase inhibitors cause a decrease in systemic vascular resistance and pulmonary capillary wedge pressure and an increase in cardiac output without increasing heart rate or myocardial oxygen demand. These hemodynamic changes are related to plasma concentration.

Milrinone is the phosphodiesterase inhibitor most commonly used in practice today because it has a shorter half-life than inamrinone and is less likely to cause thrombocytopenia. It undergoes renal elimination with an elimination half-life of 1 to 3 hours in patients with normal renal function; steady-state concentrations are reached in 4 to 6 hours if initiated without a loading dose. The risk of hypotension occurring is higher when a loading dose is given. Milrinone may be given as an initial intravenous (IV) bolus dose of 50 μg/kg administered slowly over 10 minutes followed by continuous infusion at a rate of 0.375 to 0.75 μg/kg/min and titrated to effect. Dosage adjustment should be made in patients with severe cardiac failure or renal impairment because of the considerable reduction in clearance.^1,4,6

Cardiac glycosides: digoxin (lanoxin)

The cardiac glycoside class consists of one medication, digoxin (Lanoxin), which is used in the management of congestive heart failure. The implementation of digoxin in the treatment of congestive heart failure stems from its capacity to exert an inotropic effect on the myocardium. Cardiac glycosides reversibly inhibit the sodium potassium Na⁺,K⁺-ATPase pump located in the cardiac heart muscle, leading to a net loss of potassium and a net gain in intracellular sodium concentration. As a result, the sodium-calcium active transport system, which pumps sodium out of the cell and calcium into the cell, is activated. Elevated intracellular calcium concentrations result in further calcium secretion from the endoplasmic reticulum, ultimately stimulating the actin-myosin light chain reaction, resulting in myocardial contraction. Digoxin also has an inhibitory effect on the vagus nerve, leading to decreased heart rate and atrioventricular (AV) node prolongation. In contrast to other inotropic agents such as dobutamine and milrinone, digoxin generally does not exert hypotensive effects, unless directly caused by bradycardia.

Digoxin undergoes renal elimination. In the presence of renal insufficiency, accumulation of digoxin may occur. Generally, digitalis intoxication is diagnosed when the mean serum digoxin concentration exceeds 2 ng/mL; however, the clinical significance of this value depends on the time of ingestion and the time of serum sampling. Digoxin has a long distribution phase. It may take 4 hours after IV administration and 6 hours after oral administration for digoxin to distribute fully out of the circulatory compartment and into other regions of the body. Serum sampling of digoxin before the distribution phase may give the impression that the serum concentration is greater than it actually is. Digoxin displays a very narrow therapeutic range (0.5 to 2 ng/mL), particularly in the setting of hypokalemia. Hypokalemia may potentiate the adverse effects of digoxin and render the risk of arrhythmias and death more imminent. Adequate potassium supplementation should be used to maintain the serum potassium level within a normal range.

In contrast, digitalis toxicity may cause hyperkalemia by its inhibitory actions on the Na⁺,K⁺-ATPase pump. Digoxin toxicity may manifest as serious life-threatening ventricular arrhythmias, including premature ventricular contractions, AV junctional rhythm, bigeminal rhythm, and second-degree AV blockade. Bradycardia may also occur early on in the setting of digoxin toxicity. The initial symptoms of digitalis toxicity are nausea, vomiting, anorexia, and abdominal pain. These symptoms may be due to a direct effect on the gastrointestinal tract or result from CNS stimulation of the chemoreceptor trigger zone. Other rare but possible neuropsychiatric effects may manifest as disorientation and hallucination, especially in elderly patients, and visual disturbances such as yellow-green halos. Digoxin immune Fab is the antidote used to facilitate the speedy elimination of digoxin from the body. Digoxin immune Fab is indicated in the setting of life-threatening toxicity such as ventricular arrhythmias, bradyrhythmias, ingestion of greater than 10 mg in adults or 4 mg in children, a steady state level greater than 10 ng/mL, progressive elevation of potassium, or a potassium level greater than 5 mEq/L.⁷

Ablation with radiofrequency current

Catheter ablation is very effective when atrial fibrillation (AF) is due to a single primary circuit. The procedure involves inserting a catheter into a blood vessel in the groin or the neck and guiding it toward the heart. When the tip of the catheter is placed against the part of the heart causing the arrhythmia, radiofrequency electrical current is applied through the catheter to produce a small burn about 6 to 8 mm in diameter. Patients should be adequately anticoagulated at least 1 month before the ablation procedure to prevent the formation of thrombi in the atria. The procedure carries a success rate in maintaining sinus rhythm over the next year of 30% to 90%.⁹

Implantable cardioverter-defibrillators

Implantable cardioverter-defibrillators (ICDs) have been used since the 1980s to cardiovert, to terminate ventricular tachycardia (VT), and to provide backup pacing for bradycardia. ICDs are indicated for the following conditions:

Of patients with ICDs, 40% to 70% require antiarrhythmic drug therapy, which puts them at risk for drug-ICD interactions.¹⁰

Quinidine

Quinidine, although less commonly used, is efficacious in the treatment of atrial fibrillation/flutter (AF/AFL) (Figure 21-4). The effects of quinidine on the AV node are bimodal. At lower concentrations, quinidine has antivagal properties, enhancing AV nodal conduction. At higher concentrations, the AV nodal conduction is slowed down. Because of difficulty in predicting response to quinidine, it is important to initiate a rate-controlling agent first. Quinidine should be used with caution in patients with preexisting asthma, muscle weakness, or infection with fever because hypersensitivity reactions to this medication may be masked by these conditions. Overdosage of quinidine has produced respiratory depression or distress, apnea, diarrhea and vomiting, seizures, hypotension, syncope, and electrocardiogram (ECG) changes.¹¹

Procainamide

Procainamide is available only as an IV formulation in the United States and is indicated for the treatment of ventricular tachycardia (VT) (Figure 21-5) that is life-threatening; because of its proarrhythmic effects, including torsades de pointes (Figure 21-6), the use of this agent for lesser arrhythmias is not recommended. In addition, procainamide has the potential to produce serious hematologic disorders, particularly leukopenia and agranulocytosis; it is used only when benefits outweigh the risks. Procainamide has also been used to convert AF/AFL to sinus rhythm. It is necessary to monitor levels of both procainamide and its active metabolite N-acetyl procainamide (NAPA) for efficacy and toxicity. An adverse effect unique to procainamide is the development of lupus erythematosus–like syndrome, which can manifest with pleural or abdominal pain, myalgias, arthralgias, pleural effusion, pericarditis, fever, chills, and skin lesions. Lupus erythematosus–like syndrome occurs in 30% of patients after prolonged administration of procainamide, especially in slow acetylators, who are at risk of accumulating the hydroxylamine metabolite responsible for the pathogenesis of this syndrome. If the lupoid syndrome does not resolve with discontinuation of procainamide, treatment with corticosteroids may be warranted.⁴

Disopyramide

Disopyramide is indicated for the treatment of life-threatening VT; it is also used for the treatment of paroxysmal supraventricular tachycardia (PSVT). Treatment with disopyramide should be initiated in the hospital. Patients with AF/AFL must receive digoxin therapy to achieve an adequate serum digoxin level before administration of disopyramide to ensure there is no further elevation of ventricular rate. Potassium should be corrected before initiation of therapy because the drug may be ineffective in patients with hypokalemia, and its toxic effects may be enhanced in hyperkalemia. Disopyramide may cause or aggravate congestive heart failure or episodes of hypotension because of its negative inotropic properties. Overdose with disopyramide may be followed by apnea, loss of consciousness, cardiac arrhythmias, and loss of spontaneous respirations requiring mechanical ventilation or other vigorous treatment modalities. This agent has limited use because of its anticholinergic side effects, including dry mouth, difficulty in urination, dizziness, tachycardia, hyperthermia, and blurred vision.⁴

Lidocaine

Lidocaine is used frequently to treat ventricular arrhythmia (VA) occurring during cardiac surgery or after an acute myocardial infarction. After administering IV bolus doses (owing to its short half-life of approximately 1.5 to 2 hours), continuous infusion is necessary to maintain sinus rhythm. Lidocaine is metabolized extensively in the liver to two toxic metabolites, monoethylglycinexylidide and glycinexylidide; these metabolites display antiarrhythmogenic properties but are also highly prone to seizure activity. Patients need to be monitored vigilantly for signs of seizure, such as tremors.¹¹ Other CNS side effects associated with lidocaine are insomnia, drowsiness, ataxia, agitation, and dysarthria. Caution should also be exercised in patients with hepatic failure or congestive heart failure because the rate of drug clearance is significantly reduced in either condition. Lidocaine infusions lasting longer than 24 hours may prolong the half-life of lidocaine to approximately 3 hours leading to a greater risk of lidocaine accumulation and toxicity. In the setting of lidocaine infusion longer than 24 hours, the infusion rate should be reduced by approximately 50%. Lidocaine has also been implicated in causing respiratory depression and arrest.⁴

Mexiletine

Mexiletine has a mechanism of action similar to lidocaine and is available as an oral formulation. It is indicated for the treatment of life-threatening VAs. Because of its anesthetic properties, it is also used at lower doses to reduce neuropathic pain associated with diabetic neuropathy. In controlled trials, the most frequent adverse events were gastrointestinal disturbances (41%), tremor (12%), and lightheadedness and difficulty in coordination (more than 10%). Dyspnea and respiratory problems occurred in 5.7% of patients. Coma and respiratory arrest may occur with massive overdoses.¹¹

Tocainide

Tocainide is the oral congener of lidocaine and is used to treat VAs and may also be used to treat myotonic dystrophy and trigeminal neuralgia. Tocainide carries a U.S. Food and Drug Administration (FDA) black box warning (so called for the black border surrounding the warning located in the manufacturer information sheet or the package insert) for causing pulmonary disorders, including pulmonary edema, fibrosing alveolitis, pneumonitis, and respiratory arrest (0.11%). These pulmonary manifestations are detectable on radiographic studies within 3 to 18 weeks of therapy. Another black box warning is for blood dyscrasias, which are not that prevalent (0.18%) but are associated with a fatality rate of up to 25%.⁴

Flecainide (tambocor)

Flecainide (Tambocor) is indicated for the prevention of paroxysmal AF/AFL associated with disabling symptoms and PSVT, including AV nodal reentrant tachycardia, AV tachycardia, other supraventricular tachycardia (SVT) in patients without structural heart disease, and sustained VT. It is efficacious in suppressing AF in 61% to 92% of patients treated. Flecainide has a long half-life, and the dose should not be increased more often than every 4 days. Flecainide was one of the antiarrhythmics studied in CAST in patients with asymptomatic non–life-threatening arrhythmias occurring 6 days to 2 years after documented myocardial infarction. Flecainide contributed to an excessive mortality or nonfatal cardiac arrest rate of 5.1% versus 2.3% for its matched placebo. Long-term oral prophylaxis with an antiarrhythmic agent poses a great risk of adverse events, and relapse rates are high. Also, flecainide elimination is affected by urinary pH, leading to either toxic or subtherapeutic levels. Alkaline pH decreases and acidic pH increases renal excretion of flecainide.⁴

The “pill-in-the-pocket” approach is the alternative treatment of recurrent arrhythmias, in which a pill is taken by the patient at the time of onset of palpitations. One study assessed this approach in the conversion of AF to sinus rhythm with class IC agents, using either flecainide or propafenone as a single oral dose to convert patients to sinus rhythm out of hospital. Flecainide was shown to be equally effective for pill-in-the-pocket treatment of recurrent AF, with a 94% efficacy rate.¹³

Propafenone (rythmol)

Propafenone (Rythmol) seems to be comparable to other antiarrhythmics in preventing PSVT and maintaining sinus rhythm after successful cardioversion. It is considered a first-line agent for conversion of recent-onset (less than 48 hours) AF, with efficacy rates of 60% to 90%. Therapy is 15% to 30% less effective in patients manifesting symptoms of AF for more than 48 hours. Propafenone displays nonselective β-blocking activity, and it generally should not be used to treat patients with asthma or bronchospastic disease because β-blocking properties may inhibit bronchodilation. The highest concentrations of the drug are found in the lungs (10-fold higher than in the heart muscles or liver and 24-fold higher than in the kidneys).¹¹

β blockers

Propranolol (Inderal), metoprolol (Lopressor), atenolol (Tenormin), and nadolol (Corgard) are available as IV and oral formulations; esmolol (Brevibloc) is available only in the intravenous form. These agents have negative dromotropic activity but are more commonly used for negative chronotropic properties in AF/AFL and to prevent or convert SVT to normal sinus rhythm. β blockers should not be used in settings of acute decompensated heart failure because they can exacerbate symptoms of heart failure. However, after the symptoms of heart failure are stabilized, β blockers may be initiated at lower doses. In settings in which patients with airway disease are overly sensitive to the bronchoconstrictive effects of β blockers, esmolol may be a convenient selection because of its β₁-selective property. Because of the short half-life of esmolol (approximately 10 minutes), one may titrate the dose to meet the patient’s therapeutic and safety goals.

Amiodarone (cordarone)

Amiodarone (Cordarone) is effective in the management of ventricular and supraventricular arrhythmias. In the past, the life-threatening adverse effects of amiodarone prevented it from being used as a first-line agent; it was reserved for patients with life-threatening VAs. Amiodarone seems to exhibit greater efficacy and a lower incidence of proarrhythmic effects than class I or III antiarrhythmics. Today, amiodarone has become a mainstay in the management of AF, VF, and VT.

Amiodarone-induced pulmonary toxicity warrants substantial concern when treating patients with arrhythmias. The main caveat associated with amiodarone is its distinctive side-effect profile.⁵ Baseline parameters that must be obtained before starting therapy, along with incidences of various side effects, are presented in Table 21-7. Pulmonary toxicity is quite common, as evidenced by cough and by local or diffuse infiltrates on chest radiographs, and occurs at a rate of up to 20%. Amiodarone-induced pulmonary toxicity is managed best by discontinuation or by corticosteroid therapy; in some cases, fatalities of approximately 10% have been reported ¹¹ In addition, amiodarone is probably regarded as one of the most potent inhibitors of the cytochrome P450 (CYP450) 3A4 isoenzyme system, and it inhibits CYP2C9 and CYP2C19 (hepatic drug-metabolizing enzymes); concomitant prescription medications, herbals, and over-the-counter products must be evaluated for detection of severe, often life-threatening interactions (Table 21-8).

Trimethoprim ↑ AUC and C_max of dofetilide by 103% and 93% → concomitant use is contraindicated Verapamil ↑ peak plasma concentration of dofetilide by 42%, ↑ occurrence of torsades de pointes → concomitant use is contraindicated Sotalol Thioridazine/mesoridazine/pimozide/ziprasidone/ranolazine Concurrent use with all class III antiarrhythmics may result in ↑ risk of Q–T prolongation, torsades de pointes, cardiac arrest → contraindicated Dolasetron Concurrent use with all class III antiarrhythmics may result in ↑ risk of Q–T prolongation, torsades de pointes, cardiac arrest Ibutilide None reported   Class IV CCBs: Verapamil, diltiazem Amiodarone Cardiotoxicity with bradycardia and ↓ cardiac output β blockers Additive or synergistic effects; CCBs may inhibit metabolism of certain β blockers Cyclosporine ↑ levels of cyclosporine Cimetidine/ranitidine ↑ levels of CCBs Ritonavir ↑ levels of CCBs → concomitant use (especially with bepridil) is contraindicated Fentanyl CCBs may potentiate vasodilation associated with fentanyl → hypotension Flecainide/disopyramide Additive effects → disopyramide should not be administered 48 hours before or 24 hours after verapamil Doxorubicin ↑ levels of doxorubicin → cardiotoxicity Benzodiazepines ↑ effects of midazolam and triazolam Digoxin ↑ levels of digoxin → toxicity HMG-CoA reductase inhibitors ↑ levels of atorvastatin → ↑ risk of rhabdomyolysis, liver enzyme elevation, neuropathies Lithium With verapamil, ↓ lithium levels and toxicity; with diltiazem, neurotoxicity Quinidine ↑ therapeutic and adverse effects of quinidine; use quinidine with verapamil only when no other alternative Theophylline ↑ pharmacologic and toxic effects of theophylline Class Miscellaneous Digoxin Calcium (IV) Rapid IV infusion of calcium in digitalized patients produces cardiac arrhythmias Succinylcholine Sudden extrusion of potassium from muscle cells → cardiac arrhythmias Sympathomimetics ↑ risk of cardiac arrhythmias Diuretics Diuretic-induced electrolyte disturbances (K⁺, Mg²⁺) may predispose patients to cardiac arrhythmias Thyroid hormone Hypothyroid patient on digoxin therapy may require lower digoxin doses Quinidine Marked ↑ in levels of digoxin → toxicity Adenosine Carbamazepine Higher degree of heart block; if possible, withhold carbamazepine for at least approximately 4 days before adenosine use Dipyridamole Adenosine toxicity (hypotension, dyspnea, vomiting), owing to inhibition of adenosine metabolism by dipyridamole; when dipyridamole is used before adenosine, ↓ adenosine dose Theophylline Effects of adenosine are antagonized by methylxanthines → use larger doses of adenosine Digoxin/verapamil ↑ risk of ventricular fibrillation

Adenosine (adenocard)

Rapid administration of adenosine (Adenocard) is implemented to terminate SVTs only. Adenosine has a half-life of approximately 12 seconds, and because of its ultrashort half-life, adenosine is best administered through a central line for rapid arrival at the site of action, or, if given through a brachial line, the arm should be held in the upright position followed almost instantly by a saline flush. Bronchospasms, dyspnea, hyperpnea, and cough have been reported after administration of IV adenosine in patients with asthma and chronic obstructive pulmonary disease; these symptoms are generally benign and short-lasting.¹⁹

Epinephrine

Epinephrine, an endogenous neurotransmitter, is administered in 1-mg doses as a 10-mL solution. Epinephrine stimulates β₁-adrenergic and β₂-adrenergic receptors, which are found in dense proportions in the heart and lungs. The effect of epinephrine on α₁ receptors, located within the coronary and cerebral vasculature, is more closely correlated with efficacy. Stimulation of α₁ receptors causes vasoconstriction of the coronary and cerebral vasculature, increasing blood flow to the heart’s myocardium and the CNS. In contrast, stimulation of β₁ receptors increases cardiac heart rate, resulting in increased oxygen demand on the heart and impairing oxygen delivery to the myocardium and the CNS.

One main caveat associated with epinephrine use is the occurrence of decreased receptor affinity in the setting of metabolic acidosis. Metabolic acidosis may readily ensue during SCD, owing to hypoxic conditions leading to a shift in anaerobic respiration. At the present time, there is no recommended maximal dose of epinephrine in the management of SCD. Postresuscitation side effects include hypertension and tachycardia.

Vasopressin

Vasopressin, also known as antidiuretic hormone, is an endogenous hormone that acts as a potent vasoconstrictor. Vasopressin is administered as a one-time IV dose of 40 U. Because the effects of vasopressin have not been shown to be exceedingly different from the effects of epinephrine, this dose may be administered in lieu of the first or second dose of epinephrine when treating any form of SCD. In contrast to epinephrine, vasopressin is a nonadrenergic vasoconstrictor; its vasoconstricting properties are manifested by activation of V₁ receptors (vasopressin-1), which are found in the vasculature. Once stimulated, V₁ receptors release calcium from the sarcoplasmic reticulum in vascular smooth muscle, leading to vasoconstriction and increasing systemic vascular resistance and coronary and cerebral blood flow. In contrast to epinephrine, vasopressin receptor affinity is not compromised in the setting of metabolic acidosis. In the setting of long-term continuous infusion therapy, vasopressin may cause gastrointestinal and skin ischemia; however, in the setting of SCD, these adverse events would be unlikely.

Atropine (atropen)

Atropine (AtroPen) is indicated for certain forms of SCD, such as asystole or PEA, usually given at a dose of 1 mg as IV push, along with epinephrine or vasopressin. Atropine acts by blocking the actions of acetylcholine, an endogenous cholinergic agent. The cholinergic system is typically involved with heart rate reduction, and by blocking this effect, atropine exerts a pronounced (albeit short-lived) chronotropic effect on the heart. The recommended maximal dose of atropine used during resuscitation is 0.04 mg/kg. Because atropine affects acetylcholine globally within the body, noticeable adverse effects include meiosis, dry mouth, urinary retention, and constipation.

Sodium bicarbonate

Sodium bicarbonate is usually administered as 1 mEq/kg; however, its use is very limited. The use of sodium bicarbonate is limited to the setting in which a patient fails to respond to adequate ventilation, defibrillation, and cardiac compression or is refractory to vasopressor therapy. Sodium bicarbonate may be beneficial in patients with preexisting metabolic acidosis, hyperkalemia, tricyclic antidepressant overdose, or barbiturate or salicylate overdose. Nevertheless, subsequent dosing is guided by arterial blood gas analysis. The aim is to increase arterial pH to greater than 7.2 to minimize the adverse effects of systemic acidemia, while avoiding the adverse effects of bicarbonate therapy. If the patient is improving without any serious negative sequelae, waiting for renal bicarbonate regeneration and implementing heightened monitoring for clinical improvement may be a safer measure than administering bicarbonate. Most clinicians do not treat metabolic acidosis if the arterial pH is greater than 7.1.

The presence of carbon dioxide helps the release and delivery of oxygen from hemoglobin, also known as the Bohr effect. When comparing the oxygen dissociation curves of a serum sample with carbon dioxide and another with no carbon dioxide, oxygen is able to dissociate more readily in the former state, as depicted in Figure 21-11.

In addition, sodium bicarbonate decreases hydrogen ion concentration in the serum by reacting with it, yielding carbon dioxide and water. For this reaction to continue, the product (carbon dioxide) must be removed. Sodium bicarbonate therapy aids in increasing extracellular pH only if ventilation is sufficient to remove the carbon dioxide. If hypercapnia (excess carbon dioxide in the blood) ensues, as carbon dioxide accumulates in the serum it eventually crosses cellular membranes readily, intracellular pH may continue to decline, and further deterioration of cellular function occurs.

Magnesium sulfate

Magnesium is often implemented in the management of torsades de pointes. Although its mechanism has not been fully elucidated, magnesium may exert its pharmacologic effect by prolonging conduction time; however, its role has been clearly delineated. Intravenous magnesium may be effective whether or not a patient is eumagnesemic (having a normal serum magnesium level). The typical dose consists of 1 to 2 g and may be repeated, separated by several minutes. No maximal dose of magnesium has been determined as yet; however, patients with normal renal function are reported to tolerate up to 16 g in a 24-hour period. A continuous infusion regimen may be initiated at a rate of 0.5 to 1 g/hr. Caution is warranted when treating patients with renal insufficiency. Signs and symptoms of magnesium intoxication include the following:

Severe hypermagnesemia may result in respiratory depression or fatal respiratory paralysis, circulatory collapse, and flaccid paralysis. Absence of patellar reflex is a clinical sign of magnesium intoxication.

Endotracheal route

In the event that the IV route is inaccessible, a few agents are amenable to endotracheal delivery; these agents have come to be known by the acronym NAVEL:

The following should be done when administering the above-listed agents by the endotracheal route: