128: Beta Blocker Toxicity in the PICU: Slow Heart, Fading Mind, and Falling Sugar

(upbeat music) Welcome to PQ Doc on Call, a podcast dedicated to current and aspiring intensive. I'm Prudeep Kamad, coming to you from Children's Healthcare of Atlanta, Emory University, School of Medicine. And I'm Rahul Demania from Cleveland Clinic Children's Hospital, and we are two pediatric ICU physicians passionate about all things met at in the PQ. PQ Doc on Call focuses on interesting pediatric ICU cases and management in the acute care pediatric setting. So, let's get into our episode. Rahul, I'm really excited about today's episode. So let's welcome the folks to our episode of a 15-year-olds who presents with Brady Cardia and hypotension after intentional ingestion. So why don't we start with a board question this time, rather than the whole case? - I think that's a great idea. Let's get right into it. A 15-year-old male is brought to the emergency department after a suicide attempt and was found to be hypoglycemic, hypotensive, and difficult to arouse. Now, when you look on the monitor, there's a slow abnormal heart rhythm. So now Prudeep, what do you think is the most likely ingested drug? Is it A, clonidine, B, a calcium channel blocker, C, a beta blocker, or D, digoxin? - Rahul, this is an excellent question. And I can guarantee intensive is what taking their board soon, this question will be on the boards, okay? So I think the correct answer here is C, beta blocker ingestion. Now, beta blockers can give hypoglycemia, hypotension, Brady Cardia, as well as altered mental status. In contrast, calcium channel blockers give hyperglycemia, hypotension, but are less likely to cause altered mental status in the patient. While clonidine poisoning will cause Brady Cardia, hypotension, and altered mental status, clonidine typically doesn't affect blood sugars, if at all. And digoxin can cause Brady Cardia and impaired mental status, but it doesn't affect blood sugars. I think this is an excellent question. I think listeners should be aware, there's all these four choices, a classic Brady Cardia causing agents in pediatrics. Rahul, I can see how toxicity from beta blockers and calcium channel blockers can be so easily confused on the boards. Can you share some light on how to differentiate between these two? - Absolutely. Now, both of them cause Brady Cardia, and what I wanna do is I wanna go through the variables and discern a contrast between these two drugs. So we're gonna go through first blood pressure. Both agents are going to give hypotension. Second, heart rate. Both agents, like I mentioned, will cause Brady Cardia, but just one thing that I wanna note is the dihydropyridine calcium channel blockers, those are your nicetapine and amlotapine, actually cause a reflex tachycardia. So when we're thinking about Brady Cardia, we're primarily associating that with the non-dihydropyridine calcium channel blockers, which are verapimilondil tyazine. Now, in terms of mental status, what's unique is that beta blockers penetrate the blood brain barrier and give rise to CNS symptoms, like fatigue, drowsiness, seizures, as well as calcium channel blockers, usually do not affect mental status, unless there is hypoperfusion from low blood pressure. The next part that we have to talk about is the QRS complex. Now, QRS prolongation is typically seen with membrane stabilizing beta blockers like propanol. QRS prolongation is typically not seen in calcium channel blockers. What about the QTC? Well, the QTC prolongation is seen in beta blockers, such as sotolol, mild QTC prolongation can be seen in calcium channel blockers. However, remember, the classic association is sotolol. Now, with blood glucose, this is critical. Hypoglycemia is the hallmark of beta blocker toxicity, and hyperglycemia is seen with calcium channel blocker toxicity. In the poisoning of both agents, if you have i.e. concurrent beta blocker and calcium channel blocker toxicity, you may actually get normal glycine. Rahul, that is an excellent differentiation between the two. And I think listeners should really pay attention to this because, again, I want to emphasize this, this differentiation will be tested on the boards in some form of fashion. The hallmark of beta blocker poisoning are hypotension, bradycardia, which is conduction delay, and hypoglycemia. I want to repeat that again. The hallmark of beta blocker poisoning are hypotension, bradycardia, conduction delay, and hypoglycemia. Rahul, can you tell us a bit about the action potential for nodal and non-nodal cardiac cells? I think that's important for beta blocker poisoning. Absolutely. So I think it's important to realize that the nodal tissue in the SA node has a lower resting membrane potential of minus 60 or 70 and the initial depolarization of these cells is calcium dependent. I like to call this the phase zero. Now, what the phase zero is is it's an upstroke that is in nodal action potential, going to be caused by calcium. However, in non-nodal cardiac cells, it is going to be caused by sodium entry. Now, phase one is a downslope caused by potassium, leaving the cell. And phase two in the non-nodal is a plateau phase, caused by inward moving calcium. And phase three is a downslope all the way to the resting membrane potential. Now, the repolarization phase, remember is the potassium efflux. Now, what's interesting is that the calcium channel blockers work at the phase two. This is a plateau phase preventing the entry of calcium into the heart muscle during the action potential, lowering the force of contraction. This is so critical because basically what you're saying is that if I mess with the action potential, my mechanical activity, the contraction of the heart, is going to suffer. Calcium channel blockers also cause vasoplasia due to its activity on the L-type calcium channels, reducing intracellular calcium and preventing vascular smooth muscle relaxation. So we have to now emphasize that there is calcium channels both in the myocardium as well as in the smooth muscles. Now, beta blockers, they are a little bit different. Beta blockers primarily focus on the nodal action potential. They flatten the phase four, slowing down how fast the cell drifts towards the threshold to an action potential. And if you are slowing phase four of the nodal action potential, you get bradycardia. So let's talk about the take home. Beta blockers slow down your heart rate and they slow down the AV nodal conduction. And this is because it affects phase four of the action potential. A classic board question would be a picture given to you in the exam center and you have to label what is phase four, what is phase zero, et cetera, and make sure you are prepared for that before you walk into the exam center. All right, so sorry about the physiology interplay here, but bradyp, I really wanted to emphasize these points and I want to turn it over to you. Can you tell us a little bit now more about beta receptor function itself and the general mechanisms at play? - Absolutely. Again, I can see this as a picture presented on the boards and questions asked around this picture. So the beta receptor activate the GS or the G stimulatory protein metabolic cascade which ultimately increases heart rate and relaxes smooth muscle. Here is the overview of the cellular mechanism. Hormone binding is number one, so epinephrine or no epinephrine attach to the beta receptor on the cell surface. Signal boost is the number two. The receptor then activates the internal G protein which then activates an enzyme called agnolate cyclase. This initiates the cyclic AMP or CAMP protearchal kinase pathway. Third, the second messenger action. The enzyme converts ATP into cyclic AMP which acts as a messenger to trigger specific changes inside the cell. The cyclic AMP dependent protein kinase A phosphorylates calcium channels does increasing cellular calcium influx. Increase concentration of intracellular calcium. Increase inotropy in myocytes through calcium exchange in the sarcoplasmic reticulum. The protein kinase A also phosphorylates myocene light chains which lead to contractility in the smooth muscle cells. Now, targeted activation of beta one receptor in the heart increases SA node, AV node, and ventricular muscular firing does increasing heart rate and contractility. These two effects increase cardiac output. Hence, we see this clinical findings after vasoactives are given. By blocking the normal function of the beta receptor, there is decrease in binding of epinephrine and non-epinephrine. By blocking normal function of the beta receptor, there is decrease in binding of epinephrine and non-epinephrine at the target receptor. Blocking the receptor can be thought of as producing the opposite effect. Thus, the heart will beat more slowly and with less force and in turn, give us lower blood pressure. So Rahul, can you comment on the specific effects? of beta blockers? - Absolutely, Prithip. Now that we know the normal physiology in terms of how do beta blockers work in our body, we can extrapolate the specific effects of beta blockers. First hypoglycemia. Now beta blockers give rise to hypoglycemia because there's an inhibition of beta two leading to inhibition of glucagon secretion, as well as it's decreases the glycogenyl lysis and gluconeogenesis. Now in contrast, calcium channel blockers, they actually inhibit L type calcium channels, which release insulin from the pancreas. And because calcium channel blockers block insulin, guess what patients are gonna be? Hyperglycemia. So if you take away one point from today's episode, beta blockers, hypoglycemia, calcium channel blockers, hyperglycemia. In fact, increasing glucose in calcium channel blocker ingestion has prognostication value. It informs us that the patient with the rising glucose will require vasopressors and even mechanical support. So think about that. If you have a beta eyelet cell paralysis, that then bodes the fact that the calcium channel blocker will cause you to have vasoplesia. Now let's talk a little bit about beta blockers. Beta blockers such as propranolol can cross the blood brain barrier and give rise to CNS effects. Membrane stabilizing agents like propranolol can cause QRS prolongation on the EKG. And beta blockers such as sotolol can cause QTC prolongation due to its effect on potassium channels. I do wanna just tell you that sotolol classically was known as a beta blocker, but it is a class three anti-aridmic. Amiodarone and sotolol are your class three anti-aridmics that are going to affect potassium channels. Now after ingestion, the drug effect is seen for beta blockers six to eight hours, but what's interesting is the pharmacokinetics just go off the chain and off the charts because yes, you will see it six to eight hours, but it could be up to 24 hours. And you lose really your first ordered kinetics in elimination. One example that we see on this six to eight hour effect and then up to 24 hours is metokalol. So pretty, we've talked about physiology. We've talked a little bit about beta blockers and the clinical presentation, but I really want to get very bad side in our approach. What are some of the investigations that you're going to send if you have a patient in front of you with beta blocker poisoning? - Okay, that's a good question, Rahul. And I think besides a good history and a physical exam, the labs that we need to send include a CBC type and screen, a comprehensive metabolic panel, point-of-care glucose, lactate and a blood gas, evaluate for co-ingestion such as, you know, send a urine and extended serum toxicology screens. And many times this ingestion can have other substances that could be ingested at the same time. So such as salicylate or acetaminophen, something else may also be ingested. So you have to be careful that you're not missing something else. A 12-led EKG and continuous cardiac monitoring in the PQ is necessary for all patients who have either beta blocker or calcium channel ingestion. Now, so Rahul, so how do we manage these patients? You know, like if you get a patient in the PQ with a beta blocker ingestion, how do you kind of bring your team to manage these patients at the bedside? - Well, Pradeep, you underscored the number one point. It's a team effort, and the team effort involves also knowing the basics of pediatric critical care. Airway control, especially if there's altered mental status. Fluid resuscitation with 20 ml per kilo crystalloid boluses for hypotension before considering vasoactives. I think obtaining reliable access early on is critical and getting an arterial line in for monitoring is essential because that's really gonna be a great way not only for us to monitor the blood pressure, but also understand what is the acid-based status as our patient will be in cardiogenic shock. Literature suggests that administering atropine for symptomatic Pradeepcardia is going to be a relatively benign option, but in severe overdoses, it is going to be rather ineffective. We can also try high doses of epinephrine and nor epinephrine, especially if we have a central venous line. But I think the main state with your beta blockers is glucogon, high-dose insulin, and calcium therapy. And let's dive into each one of these. Glucogon, you're going to be giving it in five to 10 milligram IV boluses over one to two minutes, followed by an infusion of two to 10 milligrams per hour if a positive chronotropic or ionotropic response occurs. What's interesting is that glucogon binds to the GS subunit directly by bypassing the poison beta receptor and increases the adeninolate cyclase activity. Glucogon also inhibits phosphodiesterase, thereby inhibiting the breakdown of cyclic AMP resulting in increased ionotropy. So just to really take home this point, beta blockers reduce cyclic AMP. Glucogon helps you regain that cyclic AMP back. Let's talk a little bit about high-dose insulin. High-dose insulin administered at one unit per kilo, IV bolus of the regular insulin is going to be suggested. And remember, you don't want to give insulin without dextrose. So you're going to give a 0.5 gram per kilo dextrose. And typically, you're going to start a regular insulin infusion and that is going to be at one unit per kilo per hour. And it can be titrated up to 10 units per kilo per hour. And just to emphasize that this is 10 times relative the dose of what we use for patient and diabetic ketoacidosis. So this is really high-dose insulin. And we're going to monitor glucose every 15 to 30 minutes initially. And normally, an unstressed heart uses free fatty acids for energy. But when cardiac function is really depressed, the heart is going to use glucose. And what that high-dose insulin does is it facilitates glucose utilization by the heart, by the glute-four transporters. And insulin will also help with lactate uptake and it increases the release of calcium in the sarcoplasmic reticulum. So let's just summarize insulin. It is going to increase the glucose utilization by the myocardium. Increase the calcium release in the sarcoplasmic reticulum thus increasing contractility. And it is going to help with lactate uptake to make sure that your acid-based milieu is optimal at the myocardium. Let's talk a little bit about calcium therapy. When we're thinking of patients who are going to have beta blocker overdose, we are going to use calcium therapy to increase myocardial contractility. And so typically, what we'll do if the patient, especially as a central line, we will give 10 to 20 amounts of 10% calcium chloride. And if the patient doesn't have a central line, we can utilize the calcium glucone. Now, for this, I remember one of our very, very early episodes, episode five, which is all on lipid-emulsion therapy. And I want us to consider that lipid-emulsion therapy is a very, very rarely attempted case or usage of beta blocker ingestion. In fact, it is only really attempted in cases of cardiac arrest. While you are going to be cannulating the patient on Tecmo. So the 2023 American Heart Association guidelines for CPR and emergency cardiovascular care actually recommends against it. However, it is interesting to note that lipid-emulsion therapy are usually last line for these severe ingestions. Additionally, highly concentrated lipid formulations have been known to occasionally clob or foul the ECMO oxygenator. So this is really something that would be last line. Now, if we take one step back and we talk about specific beta blockers, can you run through what are the common ones that we see and what are the pathophysiologic effects? Absolutely, Rahul. You have done such a great job with the general approach to beta blocker poisoning in the PQ. So some specific beta blockers, such as propranolol, it has high lipophilicity, it can cause a strong sodium channel blockade because of its membrane stabilizing activity. So it can cause seizures and a wide QRS. Basically, we need to give a sodium bicarb bolus 1 to 2 miliculons per kilo if the QRS widens to more than 100 milliseconds. And we should avoid Class 1A or Class 1C anti-rhythmics. Now, SOTALOL is a potassium channel blocker. It prolongs QT interval and can actually induce torsads. So magnesium sulfate, 2 gram IV bolus. And we have to make sure that the serum potassium is kept greater than 3.5 closer to fourish. Maximize heart rate, overdrive pacing may be required to shorten the QT interval. Metaprolol, standard beta one selectivity is lost in overdose. Metaprolol is considered to be very selective, but in toxicity that beta one selectivity is lost. Primarily causes cardiogenic shock and bradycardia, focus heavily on high dose insulin therapy, and only vasopressor support epinephrine or non-epinephrine to overcome comparative beta. blockade. ECMO is not used for standard overdoses. It is strictly reserved as a last resort for patients who are refractory to maximal medical therapy, such as severe cardiogenic shock, persistent tissue hypo perfusion, like profound acidosis or rising lactate, intractable ventricular arrhythmias and cardiac arrest. I really loved our discussion today, Pradeep. And I think this podcast would really integrate well with episode 51. If you have not listened to episode 51, which is approach to calcium channel blocker overdose, make sure that right after this episode, you listen to it because beta blockers and calcium channel ingestions, I like to call that the toxic twins. And they love to show up on pediatric boards. And that's why we made it such a big topic for our discussion today. Yes, Rahul, I cannot agree more because I think a lot of things that we talked about today are very high ill topics on the board. So let's summarize our episode today. So the hallmark of beta blocker toxicity is hypotension, predicardia, conduction delay, hypoglycemia and mental status are also seen. Torsads can be seen with drugs like SOTALO, which block potassium channels in addition to the beta blockade. Propranolol blocks sodium channels and causes QRS prolongation. It crosses the blood brain barrier and can give rise to seizures, alter mental status and even like coma. Although calcium channel blockers will cause hypotension, they are usually associated with hyperglycemia and normal mental status until cerebral perfusion from low blood pressure prevails. All right, listeners, this concludes our episode on beta blocker toxicity. We hope you really found value in our short case-based podcast. We welcome you to share your feedback, subscribe, and place a review on our podcast. Please visit our website, Pick You Doc on Call, which showcases our episodes as well as Doc on Call management cards. And just to inform everyone, Pick You Doc on Call.org will be soon getting a website revamp. Pick You Doc on Call is co-hosted by myself, Rahul Demania, and my wonderful mentor and co-host Dr. Pradeep Kamat. Dr. Monica Gray is going to be back on the air with us next episode and we appreciate her efforts in helping with the content of this wonderful topic today. Stay tuned for our next episode. Thank you and be well. [Music]