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During cardiac arrest, drug therapy is secondary to more fundamental interventions (Box 82-2). Chest compressions and defibrillation (if appropriate) should take precedence over medications. Establishing intravenous (IV) access and administering drugs, although important, should not interrupt sustained chest compressions and ventilation.
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Patients in cardiac arrest or low cardiac output states should receive 100% oxygen as soon as possible. Oxygen will increase arterial oxygen tension and hemoglobin saturation if ventilation is supported and will improve tissue oxygenation when circulation is supported. Although exposure to 100% inspired oxygen (FIO2 = 1.0) during CPR and after resuscitation has potential toxicity, there is insufficient evidence to indicate that this occurs during adult CPR.102-104
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Epinephrine has been used in resuscitation since the 1890s and has been the vasopressor of choice in modern CPR since the studies of Redding and Pearson in the 1960s.17,105 Its efficacy lies entirely in its α-adrenergic properties.39 When epinephrine is administered during CPR, peripheral vasoconstriction results in higher aortic pressure, which causes an increase in coronary and cerebral perfusion pressures and myocardial and brain blood flows.38,106,107 Flow to other organs either does not improve or diminishes further when epinephrine is given, despite the increase in aortic pressure. Animal studies demonstrate that all strong α-adrenergic drugs (epinephrine, phenylephrine, methoxamine, dopamine, norepinephrine) and nonadrenergic vasopressors (vasopressin) are equally successful in aiding resuscitation regardless of the β-adrenergic potency. β-Adrenergic agonists without α activity (isoproterenol, dobutamine) are no better than placebo.17,34,105,108,109 α-Adrenergic blockade precludes resuscitation, whereas β-adrenergic blockade has no effect on the ability to restore spontaneous circulation.36,37 Although it has been suggested that the ability of epinephrine to increase the amplitude of ventricular fibrillation (a β-adrenergic effect) makes defibrillation easier, animal studies show that epinephrine does not improve the success of, nor decrease the energy necessary for, defibrillation.75,85 Retrospective clinical studies show no effect of epinephrine on defibrillation success.83
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β-Adrenergic stimulation during cardiac arrest is potentially deleterious. In the fibrillating heart, epinephrine increases oxygen consumption. Large doses of epinephrine increase deaths in swine early after resuscitation as a consequence of tachyarrhythmias and hypertension, an effect partially offset by metoprolol treatment.110 Despite these theoretical considerations, survival and neurologic outcome studies show no difference when epinephrine is compared to a pure α-agonist (methoxamine or phenylephrine) or to a nonadrenergic vasopressor (vasopressin) during CPR in animals or humans.111-114 Recently, it has been questioned whether any drug therapy improves outcome from cardiac arrest. One study, comparing various outcomes after out-of-hospital cardiac arrest, was not able to demonstrate any improvements after introduction of advanced life support (epinephrine, atropine, lidocaine).115 Another study demonstrated improvement in short-term outcomes (ROSC and survival to hospital admission) but no difference in survival to discharge, comparing placebo with the use of all drugs (epinephrine, amiodarone, atropine, vasopressin).116 However, this study was not powered to detect clinically meaningful differences in long-term outcome. Neither of the studies was able to isolate outcomes specifically related to individual drug administration. If any effect was found, most drug trials demonstrated only short-term outcome advantage.
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When added to chest compressions, epinephrine helps to develop the critical coronary perfusion pressure necessary to provide enough myocardial blood flow for restoration of spontaneous circulation. If invasive monitoring is present during CPR, an arterial diastolic pressure of 40 mm Hg or coronary perfusion pressure of 20 mm Hg must be obtained with good chest compression technique and/or epinephrine therapy (Table 82-2). In the absence of such monitoring, the dose of epinephrine must be chosen empirically. The standard dose used in animals and humans for many years has been 0.5 to 1.0 mg intravenously. On a weight basis, this dose is approximately 0.1 mg/kg in animals but only 0.015 mg/kg in humans. Animal studies in the 1980s suggested that higher doses of epinephrine in human CPR might improve myocardial and cerebral perfusion and improve success of resuscitation.
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Outcome studies prospectively comparing standard and high-dose epinephrine do not demonstrate conclusively that higher doses improve survival. Two randomized, blinded animal studies (1 with fibrillatory arrest and 1 with asphyxial arrest) comparing standard and high-dose epinephrine found no difference in 24-hour survival or neurologic outcome, but more of the high-dose epinephrine animals died in the early postresuscitation period as a result of a hyperdynamic state.110,117 Eight adult prospective randomized clinical trials involving more than 9000 cardiac arrest patients found no improvement in survival to hospital discharge or neurologic outcome, even in subgroups, when initial high-dose epinephrine (5-18 mg) was compared to standard doses (1-2 mg). Some of the studies and a meta-analysis suggest that there may be an improvement in immediate resuscitation with high-dose epinephrine.118
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Because of the long experience with epinephrine, it remains the vasopressor of choice in CPR. It should be administered whenever resuscitation has not occurred after adequate chest compressions and ventilation have been started and defibrillation (if appropriate) attempted (Boxes 82-1 and 82-2). High doses of epinephrine apparently are not needed as initial therapy for most cardiac arrests and potentially could be deleterious under some circumstances. Current recommendations are to give intravenous epinephrine, 1 mg in the adult or 0.01 mg/kg in children, every 3 to 5 minutes. Higher doses, given as "rescue" therapy, may be indicated in specific circumstances, or if treatment has been delayed and the standard dose seems ineffective.
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The newest addition to the pharmacologic armamentarium in CPR is arginine vasopressin. It is currently recommended as an alternative to either the first or second dose of epinephrine in a dose of 40 units IV. If additional vasopressor doses are needed, epinephrine should be used. Vasopressin is a naturally occurring (antidiuretic) hormone that, when administered in high doses, is a potent nonadrenergic vasoconstrictor, acting by stimulation of smooth muscle V1 receptors. The half-life in the intact circulation is 10 to 20 minutes and longer than epinephrine during CPR. Animal studies demonstrate that vasopressin is as effective as, or more effective than, epinephrine in maintaining vital organ blood flow during CPR.119-121 Postresuscitation myocardial depression and splanchnic blood flow reduction are more marked with vasopressin than epinephrine, but they are transient and can be treated with low doses of dopamine.122 Three randomized controlled trials and a meta-analysis have found no difference in short- or long-term outcomes with vasopressin compared to epinephrine as a first-line vasopressor in cardiac arrest.114,123-125 Overall, evidence currently suggests that, like other potent vasopressors, vasopressin is equivalent to, but not better than, epinephrine for use during CPR.
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Atropine sulfate enhances sinus node automaticity and atrioventricular conduction by its vagolytic effects. Atropine is indicated when bradycardia coexists with hypotension, ventricular ectopy, or symptoms associated with myocardial ischemia. The drug can also be used to treat second- and third-degree heart block, and slow idioventricular rates. Although atropine is frequently given during cardiac arrest associated with an ECG pattern of asystole or slow PEA, no studies provide evidence that it actually improves outcome from asystolic or bradysystolic arrest.126,127 The predominant cause of asystole and EMD is severe myocardial ischemia. Excessive parasympathetic tone probably contributes little to these rhythms during cardiac arrest in adults. Even in children, the significance of autonomic tone during arrest is doubtful. The most effective treatment for asystole or PEA is improvement in coronary perfusion and myocardial oxygenation with chest compressions, ventilation, and epinephrine. However, cardiac arrest with these rhythms has a very poor prognosis. Because atropine has few adverse effects, it can be tried in arrest refractory to epinephrine and oxygenation, but its routine use is not recommended. The recommended dose for bradycardia in adults is 0.5 mg IV every 3 to 5 minutes to a total dose of 3.0 mg. The pediatric dose for treating bradycardia is 0.02 mg/kg with a minimum dose of 0.1 mg and a maximum total dose of 1.0 mg in a child and 3.0 mg in an adolescent. The dose may be repeated every 3 to 5 minutes. When treating pulseless arrest in the adult, the dose is 1.0 mg IV every 3 to 5 minutes to a total dose of 3.0 mg. Occasionally, the use of atropine during CPR may cause a sinus tachycardia postresuscitation.
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With normal cardiovascular physiology, calcium increases myocardial contractility and enhances ventricular automaticity. For many years, consequently, calcium salts have been administered during attempted resuscitation of asystole and EMD. However, multiple clinical studies have found that calcium is no better than placebo in promoting resuscitation and survival from asystole or EMD.128,129 Calcium is not indicated for use during cardiac arrest in adults or children. It may be useful for treatment of hyperkalemia, ionized hypocalcemia, hypermagnesemia, or calcium channel blocker toxicity. If calcium is administered, the chloride salt (2-4 mg/kg) is recommended because it produces higher and more consistent levels of ionized calcium than other salts.
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Although in the past sodium bicarbonate was used commonly during CPR, there is little evidence to support its efficacy. Its use during resuscitation was predicated on the adverse cardiovascular consequences of acidosis, including impaired myocardial function, decreased catecholamine responsiveness, and peripheral vasodilatation. However, most studies have been unable to demonstrate improvement in the success of defibrillation or resuscitation with the use of bicarbonate.130,131 The observation that metabolic acidosis develops very slowly during CPR may explain the absence of effect of buffer therapy. Acidosis does not become severe until 15 to 20 minutes of cardiac arrest have passed.43,132,133
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Sodium bicarbonate use during CPR should be restricted, not only because of its lack of efficacy, but because of the documented complications from excessive use, including hyperosmolality, hypernatremia, metabolic alkalosis, and hypercapnia from CO2 liberation (Box 82-10).132,134 These abnormalities are associated with low resuscitation rates and poor survival.
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Theoretically, sodium bicarbonate could cause a paradoxical worsening of intracellular and intracerebral acidosis as the CO2 liberated during the reaction with acid readily diffuses across cell membranes and the blood-brain barrier, whereas bicarbonate diffuses much more slowly. Direct evidence for this effect has not been found. Animal studies have found no change in spinal fluid acid-base status with clinically relevant doses of sodium bicarbonate135 and no worsening of myocardial intracellular acidosis during bicarbonate administration.136 Consequently, paradoxical acidosis from sodium bicarbonate remains a concern primarily on theoretical grounds.
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Current practice suggests that sodium bicarbonate should be considered for use during CPR only in arrests associated with hyperkalemia, severe preexisting metabolic acidosis, and tricyclic or phenobarbital overdose. It may be considered for use in protracted resuscitation attempts after other modalities have been instituted. These recommendations stem from its unproven efficacy in increasing patient survival and its known side effects. When bicarbonate is used, 1 mEq/kg should be given as the initial dose and no more than half this dose given every 10 minutes thereafter. However, dosing of sodium bicarbonate should be guided by blood gas determination, whenever possible.
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Routes of Administration and Vascular Access
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The preferred route of administration of all drugs during CPR is intravenous or intraosseous. If one of these routes cannot be established rapidly because of technical difficulties, one of the other alternatives—endotracheal or intracardiac—can be used.
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The most rapidly reached and highest drug levels occur with administration into a central vein. Therefore, when a central venous catheter is available during CPR, as is often the case in the operating room, it should be used for drug therapy. However, peripheral intravenous administration is also effective. The antecubital or external jugular vein should be the site of first choice for starting an infusion during resuscitation because starting a central line usually necessitates stopping CPR. Sites in the upper extremity and neck are preferred because of the paucity of blood flow below the diaphragm during CPR. Drugs administered in the lower extremity may be extremely delayed or not reach the sites of action. Even in the upper extremity, drugs may require 1 to 2 minutes to reach the central circulation.137 Onset of action may be speeded if a peripheral drug bolus is followed by a 20 to 30-mL bolus of intravenous fluid.
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Intraosseous Administration
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The intraosseous route of fluid and medication administration, originally described in 1934,138 has regained popularity recently for emergency vascular access. During CPR, all medications and fluids used, including whole blood, have been given by the intraosseous route. This technique should be considered a temporary measure during emergencies when other vascular sites are not available.
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The technique of placing an intraosseous line is straightforward. A standard 16- or 18-gauge needle, spinal needle with stylet, or bone marrow needle is inserted into the anterior surface of the tibia, 1 to 3 cm below the tibial tuberosity. Commercially available kits can facilitate access in adults. The needle is directed to a 90° angle to the medial surface of the bone or slightly inferior to avoid the epiphyseal plate. There is a loss of resistance after the needle passes through the bony cortex of the tibia. Placement is successful if the needle is in the marrow cavity, as evidenced by its standing upright without support, and bone marrow can be aspirated into a syringe connected to the needle. The needle will lose the upright position if it has slipped into the subcutaneous tissue. Free flow of the drug or fluid infusion without significant subcutaneous infiltration also should be demonstrated (Fig. 82-5).139 There are a number of reports of successful intraosseous infusions in children, with minimal complications. Animal models have demonstrated successful reversal of hemorrhagic shock,140 effective buffering with sodium bicarbonate,141 and equal hemodynamic response to epinephrine with intraosseous and central intravenous administration.142
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Endotracheal Administration
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Drugs that can be absorbed from tracheal mucosa include lidocaine, atropine, naloxone, epinephrine, and vasopressin (Box 82-11). During CPR the rapid establishment of vascular access can be difficult, especially in the obese or in infants and small children. The endotracheal route can be used as an alternative following intubation in these settings. However, intravenous or intraosseous drug administration is the preferred route because the time to effect and the drug levels achieved are inconsistent using the endotracheal route.143-145 Better results may be obtained by administering 5- to 10-mL volumes. It is unclear whether deep injection is better than simple instillation into the endotracheal tube.32 Doses 2 to 2.5 times higher than the recommended IV dose should be administered when this route is used.
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