Thank you. I appreciate the opportunity to be here for this presentation. I also didn't have anything to do with the title, a little bit surprised with that, but I think the first speaker really outlined some of the things that I'm going to touch on, but really provided kind of a baseline for the presentation. So I have no relevant financial relationships to disclose, and the learning objectives are to discuss the mechanisms of toxicity, clinical effects, and therapeutic updates for calcium channel blocker and beta blocker overdoses, to review some of the treatment options with a focus on high-dose euglycinic insulin therapy, and to describe the use of sodium bicarb in the treatment of sodium channel blockers overdoses. So I'm not actively involved as a toxicologist these days. I've worked as a director of the Poison Center in Tampa for about 12 years, and then taught on Klintoxin when I was at the university. But I had an opportunity over the working nights to come across a multi-drug overdose patient, a 72-year-old female that presented with a past medical history of hypertension, presented with worsening medication, and had a suspected calcium channel and beta blocker overdose. And she was emergently intubated in the emergency department and admitted to the ICU. She was started on vasopressors, all three of them, epinephrine, norepi, and vasopressin, and insulin therapy was ordered. The original dose that was ordered by the attending was 0.1 unit per kilo per hour. Well, we got that switched and changed to go to the high-dose protocol that we'll talk a little bit about coming up. So the high-dose insulin therapy was initiated at one unit per kilogram per hour, and then other therapies that were ordered included glucagon and lipid emulsion. So I don't forget it at the end. I had a couple of issues about the case that I wanted to make. First of all, they didn't do GI tract decontamination, which was kind of a hallmark, especially with a large overdose. So she was intubated in the emergency department, and I think they just kind of forgot about and moved on from the GI tract decontamination and activated charcoal specifically. And again, the low-dose insulin was an issue, and when I presented them with the protocol for the high-dose insulin therapy, I got critical looks from the nurses with their head shaking, like, no, that's too much. And then I also, then the house staff arrived when I was there talking to them about it, and they were like, no, one unit per kilo is too much. And then, so there was a lot of resistance, as well as initially with the fellow who was taking care of the patient. So I feel like that's something that other folks are probably going to run into when it's ordered if the nursing staff or house staff aren't familiar with it. So the treatment overview for a calcium channel blocker and beta blockers are similar, GI tract decontamination, IV fluids, calcium vasopressors, and then the high-dose insulin eukasemic therapy, and enterolipids. The glucagon is included in the protocol or the outline for beta blockers. So we were introduced to the various types of calcium channel blockers earlier. So the ones that are indeed problematic, most problematic, are the non-dihydropyridines, the verapamil and diltiazem, where the other ones are toxic but don't present the same types of problems. So the mechanism of toxicity for the non-dihydropyridines is an antagonism of the L-type calcium channels in the myocardium, where there's a decrease in SA and AB nodal conduction frequency, and there's a reduction in the heart rate and systemic blood pressure. Whereas the dihydropyridines, there's an antagonism of the L-type calcium channel in the vascular smooth muscle that causes peripheral vasodilation and reduces systemic blood pressure. There's other effects on the pulmonary and endocrine systems where the antagonism of the L-type calcium channels in the vasculature lead to increased peripheral vasodilation, increased transcapillary pressures, and interstitial edema and ARDS are possible. The endocrine system, there's the antagonism of the calcium channels as well in the pancreas with a decreased insulin release from beta cells, resulting in systemic hyperglycemia, as was mentioned, and then also which is a poor prognostic or a prognostic sign of a poor outcome. So the calcium channel blocker patient presentations, again, hypotension, bradycardia, EKG abnormalities, myocardioschemia, ARDS, hyperglycemia, AV blocks, and junctional rhythms, again, those were mentioned earlier. And then similar types of effects, and in more severe cases, bradycardia with a dihydropyridine class of drugs. So here's a long list of the beta blockers. One particular note that occurs in a number of the categories that are seen are the, including the membrane stabilization, the vasodilatory properties, partial agonists, and CNS penetration, and alpha-adrenergic effects. The CARB-A law is the one that pops up pretty frequently in each of those except the partial agonist category. So the beta blocker mechanism of toxicity is that it slows the SA node, which initiates the heartbeat, of course, and then there's a slowing of the heart rate that allows left ventricular to fill completely and lowers the heart workload. So the beta blockers, again, slow the heart rate and lower the blood pressure, and that affects the receptors in the heart and blood vessels and causes a dilated artery and lowering the blood pressure. So the patient presentations with beta blockers include decrease in heart rate and blood pressure and blood glucose, and can result in cardiovascular collapse. EKG abnormalities, some of those were mentioned before, AV blocks, junctional rhythms, and then the prolonged PR, QRS, and QT intervals. Immediate intervention for these, again, include gastric lavage or activated charcoal or multiple dose activated charcoal or even whole bowel irrigation. Again, none of those were done in the patient that I had mentioned earlier. The IV calcium, three grams of calcium gluconate, repeat IQ 10 to 15 minutes, the maximum of nine grams. Use the calcium chloride, it would be a third of that dose. So vasopressors, I have on this slide. Typically, very large doses are needed to overcome adrenergic blockade. There has been no proven benefit of the calcium channel blocker, use of calcium channel blocker toxicity. There's no trials comparing the vasopressors to the high insulin, I use ischemic therapy. It's not recommended. The addition of multiple vasopressors, of course, that was done in the patient that I mentioned. So dopamine, norepi, epinephrine, and there are case reports of paradoxical effects with the dopamine. Norepi is a reasonable first choice for patients with hypotension. Epinephrine is more beneficial than isoproteinol for beta blocker toxicity. It's inferior to glucagon. And then phenylephrine is not used in beta blocker toxicity due to an increased vascular tone with no increase in the contractility resulting in acute failure. So the hyperglycemia, I'm sorry, hyperinsulinemia euglycemia therapy, also, I'm not sure if you pronounce it Hyatt or exactly how you refer to that. So in calcium channel and beta blocker toxicity, the cardiac myocytes shift to glucose as the predominant energy source. And in calcium channel blocker toxicity, the cardiac myocytes may become insulin resistant. In both the calcium channel blockers and beta blocker toxicity, insulin release from the beta cells is inhibited, and the administration of high dose insulin with glucose reestablishes this balance. So the protocol for this is a bolus of one unit per kilogram IV times one, and then starting the infusion of one unit per kilo per hour. You titrate that at one to two units per kilo per hour every 30 minutes to a maximum of 10 units per kilo per hour. There are cases, however, of patients that have received more than 10, maybe up to 15. I think there are some other outline cases where there's some stuff in literature where patients have gotten even more than that. One of the things that's important is, of course, the rescue, because you're giving that high doses of insulin, is to combine that with dextrose and the bolus of a half gram per kilo IV at D50W times one. And then you omit the dextrose bolus if the blood glucose at baseline is greater than 300 milligrams per deciliter. Infusion, then you move into initiating the dextrose 10 percent, D10, at 250 mils an hour and titrate to the blood glucose. And if the rate exceeds 500 mils per hour, then you can change to dextrose 20 percent. So in my shifts over the New Year's holiday, the patient, there was a call from the fellow who was interested in, because of the fluid load that the patient was requiring, was concerned and wanted to know if we could go to D50. And we were concerned about that. They had a central line. So, indeed, you can do that if you need to have fluid restriction. We also had a policy at our hospital where we could only do the concentration of insulin at one unit per mil. So we were making 100 unit in 100 mil bags and sending that up. I think that there are places that have higher concentrations. Again, it was a safety thing, a policy at our hospital where we were not able to do that. So monitoring blood glucose every 15 minutes until the insulin infusion and blood glucose are stable. Again, the goal is between 100 and 250 milligrams per deciliter. If you have hypoglycemia, then you increase the dosage or the dextrose infusion rate. And then make special note not to decrease the insulin infusion. That defeats the purpose of what you're trying to do. Monitor serum potassium every hour until the insulin is stable, and then you can move to Q6 hours. And the goal of the potassium is to have it greater than three milliequivalents, not eukalemia. I've never heard of that word before, but I borrowed that from one of my collaborators. Continue monitoring after the discontinuation of the HIAT therapy. So glucagon was ordered in our patient and was receiving it routinely, and it's questionable as to whether it really did anything. Although I should say I didn't mention the earlier part of the case. After six hours, the patient of being on the high-dose, high-insulin therapy, the patient was, the vasopressors that she was on were essentially eliminated. She did not need it. So it had an improvement over the first, in the first six hours. So the mechanism for glucagon is that it increases adenocyclase activity, resulting in increased cyclic AMP in the pathway independent of the beta receptors mediated G protein. The result is increased heart rate, cardiac output, and systemic blood pressure. So our patient, as I started to mention, was receiving glucagon. It was discontinued only because we ran out of glucagon. We were making it so often, and basically we just didn't have any more that wasn't available to give the patient. So with the title, I kind of struggled with the thing about add the salt, hold the sugar, and really had a revelation. And I don't know why I didn't think of it earlier, because 40 years ago, we were using sodium bicarbonate to alkalize the blood in patients that had overdoses from sodium channel blockers, the most prominent one would be the tricyclic antidepressants. So these are the agents that can produce or do produce sodium channel block A. So when you have a wide QRS complex, the alkalization with sodium bicarb, that's the salt, and or hyperventilation, with your goal of going to 7.45 to 7.55, not above that, but that's your goal in treating those patients. In severe cases, QRS widening, unresponsive to alkalization, you could actually give a bolus of hypertonic saline, at least you can consider that. And for ventricular arrhythmias, the serum alkalization with sodium bicarb initially, and then would move to antiarrhythmics if they're not responsive to that. So I'd also like to put a pitch in, and the fellow that I worked with was put in contact with our poison control center and had multiple consultations with the on-call toxicologist, and I think she had a homegrown box from where she trained that she also consulted about the case as well. So I would encourage you to, if you're dealing with these cases, to be certain to utilize that resource in managing these cases. And my references, and I'd like to acknowledge my colleague, Jeremy Lund, who contributed and helped with this presentation, and then also the fellow that was involved with the case, Dr. Goyack. Thank you.

toxicology

case study

insulin therapy

sodium bicarbonate

poison control centers