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Airway and ventilation should be maintained with endotracheal intubation if necessary. Because laryngoscopy may induce a vagal response, it is reasonable to give atropine prior to intubation of the bradycardic patient. This is particularly true for children who are more susceptible to this complication. The initial treatment of bradycardia and hypotension consists of atropine and intravenous fluids. These measures will likely be insufficient in patients with severe toxicity but may suffice in patients with mild poisoning or other etiologies for bradycardia.
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Gastrointestinal decontamination is warranted for all persons who have ingested significant amounts of a β-adrenergic antagonist. Induction of emesis is contraindicated because of the potential for catastrophic deterioration of mental status and vital signs in these patients, and since vomiting increases vagal stimulation and may worsen bradycardia.196 Orogastric lavage is recommended for patients with significant effects such as seizures, hypotension, or bradycardia if the patient presents in a time frame when the drug is still expected to be in the stomach. Orogastric lavage is also recommended for all patients who present shortly after ingestion of large (gram amount) ingestions of propranolol or one of the other more toxic β-adrenergic antagonists (ie, acebutolol, betaxolol, metoprolol, oxprenolol, sotalol). Orogastric lavage causes vagal stimulation and carries the risk of worsening bradycardia so it is reasonable to pretreat patients with standard doses of atropine. We recommend activated charcoal alone for persons with minor symptoms following an overdose with one of the more water-soluble β-adrenergic antagonists who present later than one hour following ingestion. Whole bowel irrigation with polyethylene glycol should be considered in patients who have ingested sustained release preparations (Antidotes in Depth: A2).
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Seizures or coma associated with cardiovascular collapse is treated by attempting to restore circulation. Seizures in the patient with relatively normal vital signs should be treated with benzodiazepines followed by barbiturates if benzodiazepines fail. Refractory seizures are rare in β-adrenergic antagonist overdose.
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Patients who fail to respond to atropine and fluids require management with the inotropics discussed below (Fig. 62–4). When time permits, it is preferable to introduce new medications sequentially so that the effects of each may be assessed. We recommend glucagon followed by calcium, and high-dose insulin euglycemia therapy. In the critically ill patient, there may not be enough time for this approach and multiple treatments may be started simultaneously. If these therapies fail, we suggest starting a catecholamine pressor and phosphodiesterase inhibitors. Advanced hemodynamic monitoring, when available, is advisable to guide therapy for all patients receiving catecholamine pressors or phosphodiesterase inhibitors. Lipid emulsion therapy should be given to patients with severe toxicity or cardiac arrest. Mechanical life support with intra-aortic balloon pump or extracorporeal circulation may be lifesaving when medical management fails and is most effective when started early.
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Cardiac glucagon receptors,220 like β-adrenergic receptors, are coupled to Gs proteins. Glucagon binding increases adenyl cyclase activity independent of β-adrenergic receptor binding.227 The inotropic effect of glucagon is enhanced by its ability to inhibit phosphodiesterase and thereby prevent cAMP breakdown.149
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There are no controlled trials of glucagon in humans with β-adrenergic antagonist poisoning.12,25 Nevertheless, with more than 30 years of clinical use,107,217 glucagon is still recognized as a useful treatment of choice for severe β-adrenergic antagonist toxicity.96,163,206,222 This is supported by animal models,62,106,132 and a case series suggesting that glucagon is also effective in correcting symptomatic bradycardia and hypotension secondary to therapeutic β-adrenergic antagonist use.134 Glucagon is a vasodilator, and in animal models of propranolol poisoning it is more effective in restoring contractility, cardiac output, and heart rate than in restoring blood pressure.12,132
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The initial adult dose of glucagon for β-adrenergic antagonist toxicity is 3 to 5 mg given slowly over 1 to 2 minutes. The initial pediatric dose is 50 µg/kg. If there is no response to the initial dose, higher doses up to a total of 10 mg may be used. Once a response occurs, a glucagon infusion is started. Most authors recommend using an infusion of 2 to 5 mg/h, although many authorities recommend glucagon infusions as high as 10 mg/h. We suggest that the glucagon infusion be started at the “response dose” per hour. Thus, for example, if the patient receives 7 mg of glucagon before a response occurs, the glucagon infusion should be started at 7 mg/h. When a full 10 mg dose of glucagon fails to restore blood pressure and heart rate and the diagnosis of β-adrenergic antagonist toxicity is probable, we still recommend starting an infusion of glucagon at 10 mg/h as glucagon will have synergistic effects with subsequent antidotes. Glucagon may cause vomiting with risk of aspiration. Other adverse events of glucagon in this setting include hyperglycemia and mild hypocalcemia87 and these should be treated appropriately if they develop. Patients also develop rapid tachyphylaxis to glucagon, and the need for increasing doses and additional therapies should be expected, even when patients initially respond (Antidotes in Depth: A18).
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Calcium salts effectively treat hypotension but not heart rate in animal models of β-adrenergic antagonist toxicity.114,128 Calcium chloride successfully reverses hypotension in patients with β-adrenergic antagonist overdose27,161 and in combined calcium channel blocker and β-adrenergic antagonist toxicity.76 The adult starting dose of calcium gluconate is 3 g of the 10% solution given intravenously. We recommend using up to 9 g of calcium gluconate if needed. The initial dose of calcium gluconate in children is 60 mg/kg up to 3 g. This may be repeated up to a total of 180 mg/kg (Antidotes in Depth: A29).
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High-dose insulin, euglycemia therapy improves cardiac function following cardiac surgery65 and survival following myocardial infarction.49,137, 138, and 139 There is evidence that high-dose insulin combined with sufficient glucose to maintain euglycemia is beneficial in β-adrenergic antagonist poisoning. In a canine model of propranolol toxicity, all six animals treated with insulin and glucose survived compared with four out of six in the glucagon group, one of six in the epinephrine group, and no survivors in the sham treatment group.99 Insulin plus glucose was markedly more effective than vasopressin plus epinephrine in a porcine model of propranolol toxicity. In that experiment, all five animals in the insulin group survived the 4-hour protocol and all five in the vasopressin plus epinephrine group died within 90 minutes.82 In a rabbit model of severe propranolol toxicity, high-dose insulin was more effective than lipid emulsion in restoring blood pressure and heart rate, but there was no difference in survival.71 Clinical experience with high-dose insulin for β-adrenergic antagonist poisoning is increasing but still limited to case reports and case series.47 Improvements in heart rate and blood pressure following high-dose insulin are reported in patients with isolated overdoses of metoprolol, nebivolol, and propranolol.84,158,201 High-dose insulin was also effective in combined poisoning with β-adrenergic antagonists and calcium channel blockers.84,228
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High-dose insulin is simple to use, safe (with appropriate monitoring of glucose and potassium), and does not require invasive monitoring. For these reasons, we recommend using high-dose insulin and glucose infusions for patients with β-adrenergic antagonist toxicity who have not responded to fluids, atropine, and glucagon. Although the dose of insulin is not definitively established, therapy typically begins with a bolus of 1 unit/kg of regular human insulin along with 0.5 g/kg of dextrose. If blood glucose is greater than 300 mg/dL (16.7 mmol/L), the dextrose bolus is not necessary. An infusion of regular insulin should follow the bolus starting at 1 unit/kg/h. A continuous dextrose infusion, beginning at 0.5 g/kg/h should also be started. Glucose should be monitored every 15 to 30 minutes until stable and then every 1 to 2 hours and titrated to maintain the blood glucose between 100 and 250 mg/dL. Cardiac function should also be reassessed every 10 to 15 minutes, and if it remains depressed, the insulin infusion can be increased up to 10 units/kg/h as required (rarely higher). The goal of therapy includes improved organ perfusion with improvements in cardiac output, mental status, urine output, and acid-base abnormalities. The response to insulin is typically delayed for 15 to 60 minutes so it will usually be necessary to start a catecholamine infusion before the full effects of insulin are apparent. It is important to continue monitoring glucose and electrolytes for several hours after insulin is discontinued (Antidotes in Depth: A17).
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Patients who do not respond to the preceding therapies usually require a catecholamine infusion. The choice of catecholamine is somewhat controversial. Theoretically, the pure β-adrenergic agonist isoproterenol would seem to be the ideal agent because it can overcome β-adrenergic blockade without causing any α-adrenergic effects. Unfortunately, this therapy has several potential drawbacks, which limit its efficacy. In the presence of β-adrenergic antagonism, extraordinarily high doses of isoproterenol and other catecholamines are frequently required.36,165,171,206,215 Individual case reports document isoproterenol infusions as high as 800 µg/min.166 At these high doses, the β2-adrenergic effects of isoproterenol cause peripheral vasodilation and may actually lower blood pressure.171 Nevertheless, in some animal models, isoproterenol is the most effective catecholamine and is even more effective than glucagon in reversing β-adrenergic antagonist toxicity.203,219 However, clinical experience has not shown this to be the case. In a review of reported cases, glucagon increased heart rate 67% of the time and blood pressure 50% of the time. In contrast, isoproterenol was effective in increasing heart rate only 11% of the time and blood pressure only 22% of the time. Epinephrine was more effective than isoproterenol.222 The selective β1-adrenergic agonist prenalterol may avoid some of the problems associated with isoproterenol and was used successfully to treat β-adrenergic antagonist overdose.52,109 Prenalterol would be expected to be especially effective following overdose of the cardioselective β-adrenergic antagonists.52 Prenalterol is not FDA approved and prenalterol therapy is limited as its relatively long half-life (~ 2 hours) makes titration difficult.173 Dobutamine is a β1-adrenergic agonist with relatively little effect on vascular resistance that may be useful in this setting. However, experience is limited and dobutamine is not always effective in patients with β-adrenergic antagonist overdose.165,193 In the setting of β-adrenergic antagonism, catecholamines with substantial α-adrenergic agonist properties may increase peripheral vascular resistance without improving contractility, resulting in acute cardiac failure. Severe hypertension due to lack of β2-adrenergic–mediated vasodilation is another potential adverse reaction from this so-called “unopposed α-adrenergic” effect.59 Because of these potential problems, we recommend that catecholamine use be guided by hemodynamic monitoring using noninvasive techniques such as bioimpedance or echocardiographic monitoring or direct invasive measures of determining cardiac performance. Catecholamine infusions should be started at the usual rates and then increased rapidly until a clinical effect is obtained. If advanced monitoring is impossible and the diagnosis of β-adrenergic antagonist overdose is fairly certain, it is reasonable to begin an isoproterenol or epinephrine infusion with careful monitoring of the patient’s blood pressure and clinical status. The infusion should be stopped immediately if the patient becomes more hypotensive or develops congestive heart failure.
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Lipid emulsion is a promising antidote that has a role in selected cases of severe β-adrenergic antagonist overdose. Intravenous administration of lipid emulsion is hypothesized to reduce the toxicity of lipid-soluble xenobiotics by lowering free serum concentrations of these compounds, because they partition into the lipemic component of blood and improve the bioenergetics of the heart. Lipid emulsion has proven effective in animal models of poisoning with propranolol, a highly lipid soluble β-adrenergic antagonist, but not those that are water-soluble such as atenolol or metoprolol.29,31,32,34 Lipid emulsion was less effective than high-dose insulin in restoring heart rate and blood pressure in a rabbit model of propranolol poisoning.71 Human experience with the use of lipid emulsion in β-adrenergic antagonist overdose is limited, but cases of dramatic recovery from cardiac arrest have been reported.33,90,182,201,205 It is reasonable to administer intravenous lipid emulsion in patients with severe toxicity from a lipid-soluble β-adrenergic antagonist that does not respond to usual therapy.34,72 The optimal dose and formulation of lipid emulsion for this purpose is unknown. One protocol calls for a 1.5 mL/kg of 20% Intralipid followed by an infusion of 0.25 mL/kg/min. The bolus can be repeated in 3 to 5 minutes if necessary. The total dose should be less than 8 mL/kg221 (Antidotes in Depth: A20).
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Phosphodiesterase Inhibitors
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The phosphodiesterase inhibitors amrinone, milrinone, and enoximone are theoretically beneficial in β-adrenergic antagonist overdose since they inhibit the breakdown of cAMP by phosphodiesterase and hence increase cAMP independently of β-adrenergic receptor stimulation. Phosphodiesterase inhibitors increase inotropy in the presence of β-adrenergic antagonism in both animal models118 and in humans.213 Although these agents appear to be as effective as glucagon in animal models of β-adrenergic antagonist toxicity,132,185 controlled dog models were unable to demonstrate an additional benefit of these agents over glucagon.131,186 Phosphodiesterase inhibitors might be useful in selected patients who fail glucagon therapy, and have been used clinically to treat β-adrenergic antagonist poisoned patients.79,103,183,184 Therapy with phosphodiesterase inhibitors is often limited by hypotension secondary to peripheral vasodilation. Furthermore, these drugs are difficult to titrate because of relatively long half-lives (30– 60 minutes for milrinone, 2–4 hours for amrinone, and ~ 2 hours for enoximone).94,154 For these reasons the phosphodiesterase inhibitors should generally only be considered for patients who have arterial and pulmonary artery pressure monitoring.
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Ventricular pacing is not a particularly useful intervention in patients with β-adrenergic antagonist toxicity, but it will increase the heart rate in some patients.95 Unfortunately, there will frequently be failure to capture or pacing may increase the heart rate with no increase in cardiac output or blood pressure.4,109,113,206 In fact, some authors have noticed that ventricular pacing occasionally decreases blood pressure perhaps secondary to loss of organized atrial contraction or due to impaired ventricular relaxation.206
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Extracorporeal Removal
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Extracorporeal removal is ineffective for the lipid-soluble β-adrenergic antagonists due to their large volumes of distribution. Hemodialysis may remove water-soluble renally eliminated β-adrenergic antagonists such as atenolol179 and acebutolol.174 Because hemodialysis is often technically difficult in poisoned patients due to hypotension and bradycardia, it is rarely utilized in patients with β-adrenergic antagonist overdose but may be considered in selected cases.
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Mechanical Life Support
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It is important to remember that the patient with circulatory failure from an acute overdose will typically recover without sequelae if ventilation and circulation are maintained until the xenobiotic is eliminated. When the preceding medical treatment fails, it is appropriate to consider the use of an intra-aortic balloon pump or extracorporeal life support (ECLS). Several case reports describe remarkable recoveries following the use of these therapies for refractory β-adrenergic antagonist toxicity21,113,146 or combined β-adrenergic antagonist and calcium channel blocker overdose.53,88,102,162,178,225 In one report, a neonate who developed refractory circulatory collapse from an iatrogenic overdose of propranolol was supported with extracorporeal membrane oxygenation (ECMO) for 5 days and survived neurologically intact.41 A case series documents experience with ECMO for patients with cardiac arrest caused by cardiovascular drug poisoning. In this series of six patients, two deaths were attributed to delayed institution of ECMO. The other four patients survived without sequelae.11 In another series, ECLS was used in 17 patients with circulatory failure following a drug overdose. Eight patients had taken β-adrenergic antagonists either alone or in combination with other cardiovascular toxins. Thirteen of the 17 patients had long-term survival. The authors conclude that ECLS is efficient and relatively safe as a last resort treatment for patients with cardiac arrest or refractory shock following a drug overdose.39 More recently, researchers compared survival with ECLS versus conventional therapy in poisoned patients with circulatory failure. Six patients in the ECLS group and ten in the conventional therapy group had ingested β-adrenergic antagonists. In this series, 12 out of 14 (86%) of the ECLS patients survived compared with 23 out of 48 (48%) in the conventional therapy group. The authors concluded that ECLS is helpful in critically ill poisoned patients who do not respond to conventional therapy.144
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Experimental Treatment
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Vasopressin is a hypothalamic hormone that acts at G protein–coupled receptors to mediate vasoconstriction (at V1 receptors), water retention (at V2 receptors), and corticotropin secretion (at V3 receptors), and may also increase the response to catecholamines. Vasopressin analogues have been used as vasopressors clinically in shock states and for patients in cardiopulmonary arrest.14,214 Vasopressin was as effective as glucagon but less effective than high-dose insulin in a porcine model of propranolol toxicity.82,83 There are no reports of vasopressin use for human β-adrenergic antagonist toxicity.
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The calcium sensitizers, levosimendan and pimobendan, interact with the contractile proteins to improve cardiac function and are used clinically to treat heart failure.7,119,120,159 Levosimendan is both a positive inotrope and a vasodilator and has a better safety profile than pimobendan. It is approved in Europe for use in heart failure patients and is as effective as dobutamine in increasing contractility. Levosimendan infusions allow uptitration of β-adrenergic antagonists in patients with severe heart failure.229 Levosimendan improved survival in a porcine model of propranolol toxicity121 and improved cardiac output in a murine model of metoprolol toxicity93 but was not beneficial in a murine model of propranolol toxicity.92 Calcium sensitizers are not available in the United States or Canada. They may prove to have a role in managing patients poisoned with β-adrenergic antagonists.
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Fructose 1,6-diphosphate (FDP) is an intermediate in the glycolytic pathway. FDP is able to cross cell membranes and it increases cardiac contractility.155,208 Compared with glucose infusion, FDP infusion resulted in improved survival in murine models of propranolol toxicity and verapamil toxicity.91 FDP may prove to have a role in the management of β-adrenergic antagonist poisoning, but it cannot be recommended at this time.
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Special Circumstances
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The preceding discussion applies to the generic management of β-adrenergic antagonists. Certain β-adrenergic antagonists have unique properties that modify their toxicity. The management considerations for these unique agents are discussed as follows.
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In addition to bradycardia and hypotension, sotalol toxicity may result in a prolonged QT interval and ventricular dysrhythmias including torsade de pointes. Sotalol induced bradycardia and hypotension should be managed as with other β-adrenergic antagonists. Specific management of patients with sotalol overdose includes correction of hypokalemia and hypomagnesemia. Overdrive pacing and magnesium infusions may be effective for sotalol-induced torsade de pointes.8,211 Lidocaine is also effective for sotalol- induced torsade de pointes.10 In the future, potassium channel openers such as the cardioprotective drug nicorandil may prove effective for sotalol- induced torsade de pointes.192,207,218
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Treatment of patients who have overdosed with one of the vasodilating β-adrenergic antagonists is similar to that for patients who ingest other β-adrenergic antagonists. Decisions about the need for vasopressors should be guided by clinical findings. If vasodilation is a prominent feature, high doses of vasopressors with α-adrenergic agonist properties (eg, norepinephrine or phenylephrine) may be required.78 Conversely, if β-adrenergic antagonism is prominent, xenobiotics that act to increase intracellular cAMP, like glucagon, may be needed.74,103
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It might be expected that hypertonic sodium bicarbonate would be beneficial in treating the ventricular dysrhythmias that occur with these β-adrenergic antagonist. Unfortunately there is limited experience with the use of sodium bicarbonate in this situation, and the experimental data are mixed. Sodium bicarbonate was not beneficial in a canine model of propranolol toxicity, although there was a trend toward QRS interval narrowing in the sodium bicarbonate group.130 In models with propranolol poisoned isolated rat hearts, however, hypertonic sodium chloride proved beneficial.97,98 Perhaps most compelling is the fact that sodium bicarbonate appeared to reverse ventricular tachycardia in a human case of acebutolol poisoning.44 Because sodium bicarbonate is a relatively safe and simple intervention, we would recommend that it be used in addition to standard therapy for β-adrenergic antagonist poisoned patients with QRS widening, ventricular dysrhythmias, or severe hypotension. Sodium bicarbonate would not be expected to be beneficial in sotalol induced ventricular dysrhythmias and, by causing hypokalemia, may actually increase the risk of torsade de pointes. The usual dose of hypertonic sodium bicarbonate is 1 to 2 mEq/kg given as an intravenous bolus. This may be followed by an infusion or repeated boluses may be given as needed. Care should be taken to avoid severe alkalosis or hypokalemia (Antidotes in Depth: A5).
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All patients who have bradycardia, hypotension, abnormal ECG findings, or CNS toxicity following a β-adrenergic antagonist overdose should be observed in a intensive care setting until these findings resolve. Toxicity from regular release β-adrenergic antagonist poisoning other than with sotalol almost always occurs within the first 6 hours.126,129,167 Therefore patients without any findings of toxicity following an overdose of a regular release β-adrenergic antagonist other than sotalol may be discharged from medical care after an observation time of 6 to 8 hours if they remain asymptomatic with normal vital signs and normal ECG and have had gastrointestinal decontamination with activated charcoal. Ingestion of extended-release preparations may be associated with delayed toxicity, and these patients should be observed for 24 hours in an intensive care unit. Patients who may have delayed absorption because of a mixed overdose or underlying gastrointestinal disease may also require longer observation. Sotalol toxicity may also be delayed with ventricular dysrhythmias first occurring as late as 9 hours after ingestion.156 We recommend that all patients with sotalol overdose be monitored for at least 12 hours. Patients who remain stable without QT prolongation may then be discharged from a monitored setting.