Toxicity and Effects of Beta Blockers in Toddlers

Welcome to PICU Doc On Call, A Podcast Dedicated to Current and Aspiring Intensivists.

I'm Pradip Kamat coming to you from Children’s Healthcare of Atlanta/Emory University School of Medicine and I'm Rahul Damania from Cleveland Clinic Children’s Hospital. We are two Pediatric ICU physicians passionate about all things MED-ED in the PICU. PICU Doc on Call focuses on interesting PICU cases & management in the acute care pediatric setting so let’s get into our episode:

Welcome to our Episode: A Somnolent Toddler.

Here's the case:

A 2 yo M presents to the PICU after being found increasingly sleepy throughout the day. The toddler is otherwise previously healthy and was noted to be in his normal state of health prior to today. The mother dropped the toddler off at his Grandmother’s home early this morning. Grandmother states that he was playing throughout the day, and she noticed around lunchtime the toddler stumbles around and acts more sleepy. She states that this was around his nap time so she did not feel it was too out of the ordinary. The toddler 1 hr later was still very sleepy, and the grandmother noticed that the toddler had some shallow breathing. She called mother very concerned as she also found her purse open where she typically keeps her pills. The grandmother has a history of MI and afib as well as hypertension. She is prescribed a multitude of medications. Given the child’s increased lethargy, the grandmother presents the patient to the ED. In the ED, the child is noted to be afebrile with HR 55 & RR of 18. His blood pressure is 78/40. On exam he has minimal reactivity to his pupils, he has shallow breathing and laying still on the bed. A POC glucose is 68 mg/dL. Acute resuscitation is begun and the patient presents to the PICU.

To summarize key elements from this case, this patient has:

• Drowsiness
• Bradycardia
• Normotension
• This is in the setting of being at grandma’s home and having access to many medications
• Given the hemodynamic findings and CNS obtundation, this patient’s presentation brings up concern for a clonidine or beta-blocker ingestion.
• This episode will be organized:
• Beta-Blocker poisoning
• We will also examine other medications that potentially can be toxic to a toddler (one pill can kill) present in Grandma's purse which include: TCA, CCB, Opioids, oral anti-diabetic agents, digoxin, etc.

The presence of a grandparent is a risk factor for unintentional pediatric exposure to pharmaceuticals commonly referred to as the Granny Syndrome. Grandparents’ medications account for 10% to 20% of unintentional pediatric intoxications in the United States. To kids, all pills look like candy.

• Let’s start with a multiple choice.
• An overdose of which of the following medications may mimic the presentation of Metoprolol overdose?
• A. Verapamil toxicity
• B. Ketamine toxicity
• C. Valium toxicity
• D. Lithium toxicity

The correct answer is A, verapamil toxicity.

• Verapamil is a non DHP CCB.
• It acts at the level of the SA and AV node similar to Metoprolol, a beta-1-specific antagonist.
• Both cause bradycardia and AV node block.
• Valium though a CNS depressant, can cause CV depression as well, however, would have fewer changes on the conduction system compared to a non-DHP CCB.

 What is the mechanism of toxicity with beta-blockers?

Beta-blockers are competitive inhibitors at beta-adrenergic binding sites, which results in decreased production of intracellular cyclic adenosine monophosphate (cAMP) with a resultant blunting of multiple metabolic and cardiovascular effects of circulating catecholamines.

• They attenuate the effect of adrenergic catecholamines on the heart
• Decrease inotropic and chronotropic response. Some drugs like Propranolol can act as Na channel blockers (myocyte membrane stabilizing activity) at high doses resulting in arrhythmias and seizures. Toxic doses of drugs like Sotalol can result in K channel blockade giving rise to prolonged QT and risk for torsades.
• The anti-alpha-adrenergic activity of agents like carvedilol, and labetalol can result in peripheral vasodilation and hypotension.
• In addition, beta-adrenergic receptor antagonism inhibits both glycogenolysis and gluconeogenesis, which may result in hypoglycemia.

Rahul can you tell us about the pharmacokinetics of beta-blockers:

Beta-blockers exhibit intraclass pharmacokinetic variability with regards to absorption, bioavailability, hepatic first-pass metabolism, and lipid solubility, protein binding. Drugs like propranolol are lipid soluble with a high volume of distribution and can cross the blood-brain barrier, whereas drugs like atenolol and nadolol are water-soluble and have a low volume of distribution. The onset of action for most immediate release agents is typically 2-6hours.

All beta-blockers, regardless of their designed selectivity, can lose selectivity in overdose.

Bradycardia, hypotension & conduction delays are the hallmarks of acute beta-blocker overdose. Hypoglycemia and seizures are also seen in some cases. Risk factors for toxicity include young age (unintentional -primarily seen in children < 6 years or suicidal seen in teenagers ), co-ingestion of other medications such as TCA, Ca channel blockers, and neuroleptic agents, extended-release preparations, and known cardiac disease. In many studies looking at BB overdose, Approximately 80% of exposures were unintentional.

Pradip, what would be the typical clinical presentation of a beta-blocker overdose:

Rahul, of most the patients we see are toddlers who have had unintentional exposure to the drug such as our case presentation. There is an adult who uses the prescribed medication and the child gets access to the medication. A child can present with depressed mental status, seizures, bradycardia, hypotension, and shock. Very rarely a child with underlying airway hyper-responsiveness can present with bronchospasm. Toxicity with beta-blockers is less severe (compared to channel blocker ingestion) and can be asymptomatic or present with bradycardia and drowsiness. Hypothermia, hypoglycemia, and seizures have been reported in children. Beta-blockers that are not sustained-release formulations are all rapidly absorbed from the gastrointestinal tract. The first critical signs of overdose can appear 20 minutes post-ingestion but are more commonly observed within 1-2 hours. In all clinically significant beta-blocker overdoses, symptoms develop within 6 hours.

If you had to work up this patient with a beta-blocker, what would be your diagnostic approach?

• A good history from caregivers. Exposure to beta-blockers prescribed to a parent or grandparent can lead to the diagnosis.
• Typical labs sent include: Blood gas (to asses metabolic acidosis), serum lactate, CMP (hypokalemia or hypocalcemia can worsen arrhythmias as well as to evaluate for hypoglycemia)
• EKG, cEEG in a comatose patient
• Look for co-ingestions using serum or urine comprehensive toxicological screening.
• beta-HCG in teenagers

What is the approach to managing a patient with beta-blocker overdose?

• The patient needs to be admitted to the PICU for close observation. Contact State Poison control centers for reporting and their management recommendations.

• Besides the maintenance of patient’s airway and breathing, the goal of therapy is to restore perfusion to critical organ systems by increasing cardiac output. This may be accomplished by improving myocardial contractility, increasing heart rate, or both.

• Prehospital: Activated charcoal is indicated in the first few hours especially if the patient is not altered.

• The asymptomatic patient needs observation for at least six hours for immediate release of medications whereas sotalol may require 12 hours.

• Treatment beyond monitoring is not necessary if the only manifestation is asymptomatic bradycardia.

• So Rahul, let's say the patient is bradycardic, how would you pivot your management framework?

• For patient who is bradycardia+hypotension: The first line is the judicious use of crystalloid boluses (patient can develop pulmonary edema with excessive fluids). Atropine may be considered.

• Glucagon: stimulates adenyl cyclase via the glucagon receptor instead of the blocked beta-adrenergic receptor. The effect is seen within minutes. If no improvement in ten minutes additional dose of glucagon is less likely to be effective. The typical pediatric dose is 50-150 mcg/kg IV bolus.

• Hyperinsulinemia-euglycemia (HIE) therapy: Insulin increases both inotropy and chronotropy. Regular insulin (range 1-10U/Kg/hr is used.) Start at 1U/Kg/hr and titrate upwards every 30-40 minutes till HD improvement is seen. Add dextrose to counter hypoglycemia: 0.25 g/kg of 25% dextrose IV bolus, and an infusion of 10% dextrose. Need to watch K closely. The clinical effect is typically seen in 15-30minutes.

• Vasopressors: Use high dose NE or epinephrine. One case series of 20 patients (Musselman M. et al, Ann Emerg Med. 2011) reported no significant difference in mean arterial pressure (from baseline) in patients receiving high-dose insulin euglycaemic therapy in addition to vasopressors compared to vasopressors alone.

• Lipid Emulsion Therapy: reserved for severe cases refractory to all other therapies. Mechanism: may create a “lipid sink” to pull lipid-soluble toxins out of tissues and trap them in the vascular compartment; delivers free fatty acids to the heart for improved metabolic functioning. For children, a 20% lipid emulsion is used. Typically a 1.5 mL/kg bolus is administered. if the patient shows improvement, then can consider an infusion at 0.25-0.5 mL/kg/minute until hemodynamic recovery.

Please visit our episode # 4 titled PICU Applications of Lipid Emulsion Therapy

• If all else fails- The patient may require Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) cannulation. Cardiac pacing may be effective in increasing the rate of myocardial contraction if pharmacological therapy fails.

Pradip, this was a great case. Let’s go into other medications which may be found in Grandmother’s purse and the antidotes which are commonly employed in cases of ingestion:

• Clonidine: Grandma's purse may have clonidine patches or tabs (used for sleep, hypertension, etc.). Most patients present with somnolence, along with bradycardia or hypotension.
• First things first: maintain airway, breathing, and hemodynamics. Especially in this patient with marked central nervous system depression, we should consider trialing intravenous naloxone(0.1 mg/kg, maximum single dose: 2 mg). This may be repeated every one to two minutes up to 10 mg total dose. Please note, Naloxone has been utilized to treat seriously poisoned clonidine overdose patients with inconsistent results. Finally, in symptomatic patients with enteral clonidine overdose, it is important to note that HD or CRRT has a limited role. Another important point to remember in a child who may have an overdose with clonidine is to have the child fully exposed and have any adherent transdermal patches be removed.
• We advocate the early use of activated charcoal + supportive care with attention to airway, breathing, and circulation. The antidote Flumazenil can be used to reverse severe benzodiazepine toxicity.

1. ACE inhibitors → Include drugs like captopril, and enalapril, which block the conversion of angiotensin I to angiotensin II, thereby lowering arteriolar resistance to decrease BP. Mild toxicity may be produced with a single, supra-therapeutic dose; however, severe toxic effects and deaths are rare and are often attributed to co-ingestants. There are reports of children 6 years of age and younger who have ingested up to 8mg/kg captopril or up to 2mg/kg enalapril or lisinopril and remained asymptomatic. The primary toxic effect of ACE inhibitor ingestion is hypotension. Asymptomatic patients should be observed for at least four hours post-ingestion with frequent monitoring of vital signs. Hyperkalemia and hyponatremia may be seen due to the aldosterone blocking effect of ACE inhibitors.

Symptomatic or hypotensive patients should be admitted for at least 24 hours post-ingestion or until symptoms have completely resolved. Patients should be given adequate IV fluids to maintain a satisfactory blood pressure and a good urine output. Oral-activated charcoal may be given to patients who have ingested a large overdose, given they present within 1-2 hours. Although the role of naloxone in the setting of ACE inhibitor overdose remains unclear, it may be considered, especially in cases of severe hypotension where fluid overload is a concern. (Mechanism) ACE inhibitors inhibit the metabolism of enkephalins and potentiate their opioid effect, which includes lowering BP.

1. Calcium Channel Blockers
2. Watch for hypotension and bradycardia, conduction defects, and ultimately cardiovascular collapse. The patient may be asymptomatic initially. Hyperglycemia from the blockade of insulin release from the pancreas and metabolic acidosis from hypo-perfusion may be seen.
3. administration of intravenous (IV) calcium, glucagon, catecholamines, and high-dose insulin therapy. Intravenous lipid emulsion therapy lacks clear evidence for efficacy but is a consideration if all else fails. Methylene blue has been tried especially in amlodipine toxicity. In severe refractory cases, cannulation to VA ECMO has been used.
4. Oral anti-diabetic medications or sulfonyl ureas: • Binding of sulfonylurea to the sulfonylurea receptor 1(SUR1) subunit closes the ATP-dependent K channel, thus leading to insulin secretion. Can lower blood sugar to a dangerous level resulting in confusion, irritability, lethargy, tachypnea, tachycardia, sweating, hypothermia, seizures, altered mental status, coma, and even death. The patient requires observation X 24hrs or longer if an extended-release preparation is ingested. Use activated charcoal for 1-2 hours if not altered. Correct hypoglycemia with IV dextrose. Octreotide IV has been used to inhibit release of insulin.
5. Tricyclic antidepressants are now rarely used due to the wide availability of SSRIs. Overdose can cause cardiac arrhythmia (Na Channel blockade), hypotension (due to peripheral alpha-adrenergic blockade), cardiac arrest, seizures, and coma. Among patients who are asymptomatic more than 6 hours after ingestion, symptoms are unlikely to develop; however, delayed toxic effects may occur, particularly if there are co-ingestants that delay gastrointestinal motility.
6. Management includes: close monitoring of vital signs and serial examinations for evidence of anti-muscarinic toxicity and for cardiac and neurologic manifestations that can be used to guide treatment strategies. Supportive care includes maintenance of airway, breathing, and hemodynamics. Activated charcoal can be used within 1-2 hrs of ingestion. If the QRS is prolonged (>100m secs) or there is HD instability NaHCO3 bolus followed by a continuous infusion is required. Use fluids for hypotension. For fluid refractory hypotension consider vasopressors such as epinephrine or norepinephrine. Use benzodiazepine for seizures. If hemodynamic instability persists despite all the above, consider intravenous lipid emulsion therapy. For prolonged QT-MagSO4 is frequently used.
7. Opioids and other pain meds (acetaminophen, NSAIDs, aspirin, or even topical products containing methyl-salicylate, camphor): Treatment is supportive with close attention to airway, breathing, and hemodynamics. Naloxone can be used for opioid ingestion (listeners can get more details about opioid poisoning from our episode # 61). Methyl salicylate can cause nausea, vomiting, hyperthermia, blood sugar abnormalities, weakness, ringing in the ears, fast breathing rate, seizures, and coma, 1/2 teaspoon can be fatal in a toddler. NAC can be used for acetaminophen toxicity. Salicylate toxicity requires alkalization of urine as well as hemodialysis depending on the level or the presence of neurological symptoms.
8. Digoxin: Fortunately digoxin use has declined since 1990 and so has the incidence of toxicity associated with it. Digoxin increases intracellular calcium in myocardial cells indirectly, by inhibiting the sodium-potassium pump in the cell membrane. A child can present with non-specific GI symptoms (vomiting, diarrhea, abdominal pain), lethargy, and confusion followed by sinus bradycardia, AV block, and ventricular ectopy. Ventricular tachycardia and atrial fibrillation can occur with severe toxicity. Hyperkalemia may be seen with digoxin toxicity. Besides supportive care, digoxin-specific antibody fragments are used to form complexes with digoxin, which are then excreted in the urine.
9. Alcohols: Perfumes, hand sanitizers (used extensively during the pandemic) and mouthwashes contain concentrated alcohol. Acute alcohol poisoning can result in vomiting, seizures, hypoglycemia, hypothermia, respiratory insufficiency, and unconsciousness. Treatment is mainly supportive.
10. Nicotine: Exposure to liquid nicotine used to refill e-cigarettes or nicotine gum in a small child can be deadly. With an estimated median lethal dose between 1 and 13 mg per kilogram of body weight, 1 teaspoon (5 ml) of a 1.8% nicotine solution could be lethal to a 90-kg person. Low dose exposure can result in tachycardia, vomiting well as truncal ataxia, and even seizures. With a higher dose, we see signs of muscarinic cholinergic toxicity, including extreme secretions and gastrointestinal disturbance. The highest level of poisoning can result in NM blockade, respiratory failure, and even death. Treatment is supportive although atropine can be used to combat cholinergic activity.
11. Before we get into our summary for this episode, we want to stress the importance of having a collaborative approach in the management of these ingestions, notifying poison control, toxicology, coordinating care with PICU team members including pharmacists, as well as having proactive communication with ECMO primers are tenants of high-quality care.

Rahul, let’s go ahead and summarize today’s episode:

1. Most patients who develop toxicity from beta-blocker overdose do so within two hours of ingestion, and virtually all do so within six hours. Bradycardia and hypotension are the most common effects. Cardiogenic shock and ventricular dysrhythmias can occur with severe overdose. Hypoglycemia is seen more often in children.
2. Grandma’s purse can be a potpourri of medications that can be very toxic to a toddler resulting in the “one pill can kill” phenomenon. In this episode, we have described a few of the medications individually but many times this may not be the case and the toddler may have ingested more than one type of medication thus further complicating the diagnosis as well as the management. Sticking to good supportive care, consultation with state poison control as well as a toxicologist is helpful in such cases.

As pediatric intensivists, we are pediatricians at heart and our job is to educate parents/grandparents to keep children safe: Keep all purses out of reach of small children, Keep...