This case unfolded in such a way that it really invoked critical thought and differentials in my mind. I worked with my attending and the tox consultant to “best guess” my way through his care—trying to make a diagnosis based on response to treatment. It was really interesting to me and I learned much about the presentation and treatment of an overdose of these classes of drugs while seeing it all happen in front of me. So, there are many “correct” answers to the questions posed. The one keyed as correct is a reflection of the situation as it was at that time and thought to be the best choice based on that. I’m sure all of the very intelligent members of my class have comments about the varying degrees of how right and wrong each answer is to these questions and that’s great! I hope it inspired as much thought in the critique of answers as it did in me while working through it in the ED.
1.) Based on this patient’s clinical presentation, which of the following would be the most likely medication/class of drug suspected as an overdose?
a.) beta blocker
b.) calcium channel blocker
Here are the key elements in this patient for this question:
He had no improvement in his mental status or hemodynamics with Narcan. He had no notable PVC’s or characteristic “swoop” of digoxin on EKG and his QRS complexes were wide, not narrow. He had no resolution of his bradycardia with D50 in the field. He presented with cool extremities and a low body temperature.
DIFFERENTIAL DIAGNOSIS — Many drugs can cause profound hypotension or bradydysrhythmia in overdose. Calcium channel blockers, digoxin, clonidine, and cholinergic agents must be considered when evaluating bradydysrhythmia potentially caused by a toxic ingestion.
Calcium channel blockers are less likely than beta blockers to produce alterations in mental status, and frequently do not do so unless the patient is in profound shock. Hyperglycemia occurs more often with calcium channel blocker toxicity, while beta blockers are associated with hypoglycemia.
Nausea and vomiting occur more often with digoxin toxicity than beta blocker toxicity. Digoxin may cause characteristic changes in an electrocardiogram, such as scooped ST segment depressions. Digoxin is more likely to produce rhythms of increased automaticity, such as atrial tachycardia with atrioventricular block, premature ventricular contractions, or ventricular arrhythmias.
Clonidine produces a constellation of signs that can resemble opioid overdose, including somnolence and miosis, but are accompanied by hypotension and bradycardia.
Overdose of a cholinergic agent can present with bradycardia but also includes other characteristic features (salivation, lacrimation, urination, defecation, GI upset, and muscle excitability).
Overdose of diabetic medications would most likely be reversed by intravenous glucose administration and would not cause persistant bradydysrhythmia.
2.) While considering all clinical information in this case, which of the following clinical findings helps to identify the most likely overdosed medication?
a.) core body temperature
b.) electrocardiogram findings
c.) mental status
d.) peripheral pulses / capillary refill
e.) serum glucose values
Key considerations here:
A low body temperature can be just a reflection of the environment. It is not specific. EKG findings are rarely specific to one exact drug and bradycardia can develop for many reasons.
A person’s mental status can be altered by medications, but it will be altered if a patient is not perfusing their brain well as in the case of significant hypotension.
A diminished capillary refill will be present in any hypotensive patient when compensatory mechanisms try to preserve central blood flow.
This patient is not a diabetic. He required many boluses of glucose. He was found with an empty bottle of medication for “high blood pressure”.
Physical findings — Most patients who overdose on beta blockers become symptomatic within two hours following ingestion, and nearly all develop symptoms within six hours. Exceptions to this general rule include ingestions of sustained release medications and sotalol. In these cases, delayed toxicity up to 24 hours after ingestion can occur. Bradycardia and hypotension are the most common effects, and in severe overdoses can result in profound myocardial depression and cardiogenic shock. Ventricular dysrhythmias are seen more frequently following propranolol and acebutolol exposures, probably because of the increased membrane-stabilizing activity (MSA) of these agents. Other potential effects of severe toxicity include mental status change, seizure, hypoglycemia, and bronchospasm.
Mental status changes, including delirium, coma, and seizures, occur most frequently in patients with severe hypotension, but can occur in those with normal blood pressure. Similarly, respiratory depression usually occurs in hypotensive, comatose patients, but has been reported in awake patients. Specific agents, particularly propranolol, are associated with neurologic effects in the absence of cerebral hypoperfusion.
Patients with severe peripheral vascular disease described a variety of complications including worsening claudication, cold extremities, absent pulses, and, in some cases, cyanosis and impending gangrene. Raynaud’s phenomenon can also be a manifestation of nonselective beta blockade. It was thought that both the reduction in cardiac output and blockade of beta-2-receptor-mediated skeletal muscle vasodilation contribute to the vascular insufficiency. Beta blockers with beta-1 selectivity or ISA do affect the peripheral vessels to the same degree as the nonselective drugs.
Electrocardiogram — Beta blockers decrease conduction velocity across the atrioventricular (AV) node, resulting in PR prolongation; they also slow automaticity within the sinoatrial (SA) node, causing bradycardia. In severe poisoning, the electrocardiogram can show ANY bradydysrhythmia, and can progress to asystole.
Following overdose, manifestations of toxicity are observed in varying degrees, depending on the specific agent and dose involved. In addition to beta-adrenoreceptor blockade, three properties that affect toxicity include the membrane stabilizing activity (MSA), lipophilicity, and intrinsic sympathomimetic activity (ISA) of the ingested agent.
• Membrane stabilizing activity (MSA) – Membrane stabilizing agents (eg, propranolol, acebutolol) inhibit myocardial fast sodium channels, which can result in a widened QRS interval and may potentiate other dysrhythmias.
• Lipophilicity – Beta blockers with high lipid solubility (eg, propranolol) rapidly cross the blood brain barrier into the central nervous system, predisposing to neurologic sequelae such as seizures and delirium.
• Intrinsic sympathomimetic activity (ISA) – Many agents demonstrate a partial agonist effect at the beta receptor site, resulting in less bradycardia and hypotension in therapeutic and supratherapeutic doses. Bronchoconstriction is also less likely to occur with compounds that possess intrinsic sympathomimetic activity (ISA), or beta-1 selectivity. However, the protective effects of ISA do not completely prevent cardiovascular toxicity following intentional or accidental overdose.
3.) Once the patient is stabilized, what treatment should be initiated and was recommended by poison control?
a.) activated charcoal
b.) calcium infusion
c.) continuous intravenous hydration
e.) whole bowel irrigation
Key points in this question:
We don’t know the time interval between ingestion and presentation.
A patient in resus always has fluids running, but you need to remember to look up and take stock in just how much fluid they are getting. A 49 year old hypertensive male probably has some LV dysfunction and may not benefit from liters of fluid.
First things first…the usual O2, IVF, give D50 for any further low blood sugars and address the bradycardia and hypotension.
Treat hypotension with intravenous (IV) boluses of isotonic fluid; treat symptomatic bradycardia with atropine. Atropine is given in a dose of 0.5 to 1 mg every 3 to 5 minutes up to a total of 0.03 to 0.04 mg/kg.
IV fluid and atropine often do not completely reverse the cardiotoxic effects of beta blocker overdose. In such cases, add the following treatments in succession based upon patient response:
• IV calcium salts
• High dose insulin and glucose infusions
• Phosphodiesterase inhibitors
Glucagon — Despite limited data, glucagon is considered first-line, antidotal treatment for beta blocker overdose [13,14]. Intravenous (IV) glucagon is given as a slow bolus dose followed by continuous infusion. An initial bolus of 5 mg intravenously is administered over one minute; if there is no increase in pulse or blood pressure after 10 to 15 minutes, a second bolus should be administered. The initial pediatric dose is 50 micrograms/kg. An effect should be observed within 1 to 3 minutes, with a peak response at 5 to 7 minutes. If there is no observed effect after 10 minutes following a second dose, it is unlikely an infusion will provide benefit.
If there is an increase in pulse or blood pressure, an infusion is started at a rate of 2 to 5 mg/hour (pediatric dose 70 micrograms/kg/hour). The goal is to maintain a mean arterial pressure of 60 mmHg. If this cannot be achieved, additional therapies are implemented in a sequential manner, beginning with calcium salts. When used as a sole agent in humans, glucagon has been associated with treatment failures.
Vomiting is common following administration of glucagon.
Glucagon activates adenylate cyclase at a site independent from beta-adrenergic agents, causing an increase in adenosine 3′-5′-cyclic monophosphate (cAMP). Elevations in cAMP increase the intracellular pool of calcium available for release during depolarization, augmenting contractility. The successful use of glucagon to manage beta blocker toxicity has been documented in many case reports, but no controlled trials involving humans have been conducted. One review of the available controlled trials in animal models found that glucagon increased heart rate (HR), at least transiently, but had minimal effect on mean arterial pressure (MAP).
In 2006, a trial comparing vasopressin with glucagon in a swine model of propranolol overdose found no difference in survival at 4 hours. No difference was detected in HR, MAP, systolic BP, or cardiac output, except in the first hour, when vasopressin caused a marked increase in MAP and systolic BP. Notably, cardiac output did not improve following glucagon administration.
Calcium — A number of case reports demonstrate the efficacy of IV calcium salts in treating beta blocker toxicity. Either calcium chloride or calcium gluconate may be given.
Calcium chloride, 1 g of a 10 percent solution (10 mL), is given as a slow push, and should be administered via a central venous catheter. The dose may be repeated up to a total of 3 grams. The pediatric dose is 20 mg/kg (maximum dose is 1 g); up to 60 mg/kg may be given.
Calcium gluconate should be utilized if only peripheral IV access is available. The percentage of elemental calcium in calcium gluconate is one-third that of the calcium chloride salt, so 30 mL of a 10 percent solution should be administered as an initial dose. In children, give 60 mg/kg per dose (maximum dose is 3 g).
IV calcium salts may improve hemodynamic parameters by increasing inotropy. Animal models suggest that calcium salts increase blood pressure and cardiac output, but do not increase heart rate, following combined calcium channel blocker and beta blocker overdose.
Glucagon — Glucagon increases intracellular levels of cyclic AMP and, in animal models, has been shown to increase heart rate in calcium channel blocker toxicity . It has minimal effects on the mean arterial pressure, however. Glucagon has been effective in treating human cases of CCB toxicity
Catecholamines — In animal models and human case reports, treatment of beta blocker overdose with catecholamine infusion alone has resulted in poor outcomes. One study of insulin therapy in propranolol toxicity was terminated early when every pig in the insulin and glucose treatment group achieved the study goal of 4 hour survival, while those treated with vasopressin and epinephrine died within 90 minutes . Cardiac output (CO) in animals treated with insulin and glucose increased throughout the trial; CO in animals treated with vasopressin and epinephrine decreased until death.
Hypoglycemia must be corrected prior to initiating insulin therapy. We begin treatment in adults by administering 50 mL of 50 percent dextrose (D50W) IV, followed by an insulin bolus of 2 units/kg over 5 minutes. An insulin infusion is then started at 0.5 units/kg/hour, with a goal rate of 2 units/kg/hour. A dextrose infusion of 1 g/kg/hour is begun simultaneously.
The pathophysiology of beta-blocker intoxication is similar in many respects to that of calcium channel blocker (CCB) intoxication, for which high dose insulin and glucose has been more extensively studied. Although the mechanism is not completely understood, both CCB and beta blocker poisoning appear to interfere with myocyte metabolism. In addition, beta blockers inhibit pancreatic insulin release further reducing available glucose and diminishing CO. Insulin appears to improve inotropy by providing substrate for aerobic metabolism within the myocyte.
Though the mechanism is not completely understood, CCBs appear to disrupt fatty acid metabolism and create relative insulin resistance within the myocardium. This state of carbohydrate dependence and insulin resistance can theoretically be overcome with high-dose insulin . Animal studies of CCB toxicity have shown improved survival associated with hyperinsulinemia/euglycemia therapy compared with calcium, epinephrine, or glucagon [21,22]. Clinical experience with this approach is limited [23,24]; in one case series of four verapamil-poisoned patients, hyperinsulinemia/euglycemia therapy improved blood pressure and ejection fraction without changing heart rate . High-dose insulin therapy is also used in beta blocker poisoning.
Gastrointestinal (GI) decontamination — GI decontamination may involve activated charcoal (AC), whole bowel irrigation, or gastric lavage; therapy is based upon clinical circumstance. (See “Decontamination of poisoned adults”).
We suggest treatment with activated charcoal (AC), 1 g/kg by mouth or nasogastric tube, in all patients who present within 1 to 2 hours of a known or suspected beta blocker ingestion, unless there are contraindications to its administration. Charcoal should be withheld in patients who are sedated and may not be able to protect their airway, unless endotracheal intubation is performed first. However, endotracheal intubation should not be performed solely for the purpose of giving charcoal.
Asymptomatic patients who present more than two hours after a reported ingestion are unlikely to benefit from AC, and we do not recommend routine treatment in these patients.
The role of activated charcoal in symptomatic patients who present several hours after ingestion is more controversial. We suggest the administration of AC (1g/kg by mouth or nasogastric tube) if there are no contraindications to charcoal administration. Although there are no data to suggest improved outcomes with AC in such patients, we believe that AC is a relatively safe intervention whose potential benefits in this situation outweigh its risks.
Gastric lavage should not be routinely performed, but may be considered for patients who present within one hour following ingestion of a large quantity of medication. Large sustained or controlled release tablets may not pass through the oral gastric tube.
Whole bowel irrigation is reserved for patients who have ingested sustained release or enteric coated preparations, or have suspected drug concretions (pharmacobezoars) in the GI tract.
• Sodium bicarbonate — Sodium bicarbonate has been used successfully in the treatment of beta blocker induced arrhythmia [26,27]. Because it is a relatively safe intervention, we suggest giving it as an adjunct for patients with QRS widening.
The dose of sodium bicarbonate is 1 to 2 mEq/kg given as an IV push, which may be repeated. If treatment is effective, an infusion can be started. We mix 132 mEq of sodium bicarbonate in 1 liter of D5W and infuse at 250 mL/hour in adults, and at twice the maintenance fluid rate in children. The infusion is tapered once the arrhythmia resolves. (See “Tricyclic antidepressant poisoning”).
• Magnesium — Magnesium may be administered when ventricular arrhythmias are present or hypomagnesemia is suspected. Sotalol has a high propensity to induce ventricular arrhythmias and will often require magnesium, administered as a 2 g IV bolus or as a continuous infusion.
• Intravenous pacing — Ventricular pacing may be effective in patients with profound bradycardia, or in patients with combined beta blocker and calcium channel blocker intoxication . However, ventricular pacing frequently fails to capture, or increases the heart rate without a corresponding increase in perfusion . IV pacing can be implemented if there is no response to pharmacologic therapies, and the patient remains bradycardic and hypotensive. Some authors note a decrease in blood pressure with pacing . (See “Temporary cardiac pacing”).
• Intraaortic balloon pump — The intraaortic balloon pump has been used successfully after failure of pharmacologic management in severe cases of propranolol and atenolol overdose [30,31] and in combined verapamil-SR (sustained release) and atenolol overdose . (See “Intraaortic balloon pump counterpulsation”).
• Hemodialysis — Hemodialysis has a minimal role in the treatment of beta blocker overdose and is effective only with hydrophilic, minimally protein-bound beta blockers such as atenolol . Nadolol, sotalol, acebutolol, and atenolol are reportedly removed by hemodialysis, but metoprolol, propranolol, and timolol are not.
Hemodialysis is reserved for patients who have not improved despite aggressive medical intervention, have ingested a significant amount of a beta blocker that can be removed using dialysis (eg, acebutolol), or have ingested other cardioactive medications that may exacerbate toxicity. In such cases, the emergency clinician should contact a nephrologist early in the patient’s course to avoid delays in preparing for hemodialysis.
Continuous venovenous hemodialysis (VVHD) can be used if the patient is not able to tolerate traditional hemodialysis due to pronounced hypotension. The decision to initiate hemodialysis and the selection of the appropriate type is made in consultation with the nephrologist.
Will post soon.
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