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Emergency Medicine News:
doi: 10.1097/01.EEM.0000365878.15431.4f
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Novel Antidotes for Potentially Life-Threatening Drug Overdoses: Hyperinsulinemia-Euglycemia Therapy

Roberts, James R. MD

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Author Credentials and Financial Disclosure: James R. Roberts, MD, is the Chairman of the Department of Emergency Medicine and the Director of the Division of Toxicology at Mercy Health Systems, and a Professor of Emergency Medicine and Toxicology at the Drexel University College of Medicine, both in Philadelphia.

Dr. Roberts has disclosed that he is a member of the Speakers Bureau for Merck Pharmaceuticals. All other faculty and staff in a position to control the content of this CME activity have disclosed that they and their spouses/life partners (if any) have no financial relationships with, or financial interests in, any commercial companies pertaining to this educational activity. Lippincott CME Institute, Inc. has identified and resolved all faculty and staff conflicts of interest regarding this educational activity.

Part 2 in a Series

Learning Objectives: After participating in this activity, the physician should be better able to:

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1. Summarize how hyperinsulinemia-euglycemia therapy works in the management of patients with calcium channel blocker overdose.

2. Categorize patients with calcium channel blocker and beta blocker overdoses to determine who should receive hyperinsulinemia-euglycemia therapy.

3. Devise an organized plan of therapy for patients with calcium channel blocker and beta blocker overdoses.

Most intentional overdoses survive with aggressive supportive care and concomitant tried and true antidotes, but some patients can defy even the best attempts at resuscitation. While some overdoses require just basic cardiovascular and respiratory support, a few massive pharmaceutical overdoses are death sentences even when the patient arrives awake and talking. While the miraculous effects of naloxone and digifab are known by even the neophyte resident, some heroic antidotes lack scientific rigor, and use is based mainly on theory, supported by promising, albeit scattered and anecdotal, case reports. Nonetheless, the reputed antidotes appear to be helpful or at least reasonable in otherwise desperate situations, and their use can be considered even when the specific offending pharmaceutical is unknown.

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Last month, I discussed the potential antidote properties for lipid emulsion, a way to disable fat soluble drugs in the vascular system, including local anesthetics and perhaps antidepressants, antipsychotics, and cardiovascular preparations. Another novel approach to the otherwise hopeless calcium channel blocker overdose or perhaps even beta blocker overdose is high-dose insulin and glucose infusion. Similar to the data on intravenous lipid emulsion therapy, this intervention is not FDA-approved, but is primarily supported by animal studies and case reports buffered with sophisticated if not fancy toxicology theory. After the basics have been attended to, one might consider this last-ditch effort to reverse the cardiovascular ravages of a severe calcium channel blocker or beta blocker overdose.

Bench to Bedside Review: Hyperinsulinemia/Euglycemia Therapy (HIET) in the Management of Overdose of Calcium-Channel Blockers

Lheureux P, et al

Crit Care

2006;10(3):212

Hyperinsulinemia-Euglycemia Therapy: A Useful Tool in Treating Calcium Channel Blocker Poisoning

Levine MD, Boyer E

Crit Care

2006;10(4):149; http://ccforum.com/content/10/4/149

These articles summarize current knowledge regarding the use of high-dose insulin and euglycemia via intravenous glucose infusion (HIET) as adjunctive treatment of a severe calcium channel blocker overdose. The authors, toxicologists and emergency physicians from Belgium and Boston, believe that experimental data and positive if not remarkable limited clinical experience suggest that HIET actually may be a superior pharmacologic intervention compared with conventional therapy (calcium, adrenalin, dobutamine, and glucagon) for calcium channel blocker overdose. Both articles merit a full read by interested clinicians.

Bradycardia, conduction delay, and negative inotropy, combined with peripheral vasodilatation leading to lactic-metabolic acidosis, are pathophysiologic derangements well known to any EP. The causes are legion. A severe calcium channel blocker overdose is one offender. While not a garden-variety intentional overdose or a common denizen of the resuscitation room, a serious calcium channel blocker overdose is a tough case for anyone to manage. The derangements of calcium channel blocker toxicity are thought to be due to excessive blockade of the L-type calcium channel in the myocardium and smooth muscle of the vascular system and in the pancreas. Essentially, calcium influx into cells of the heart, blood vessels, and pancreatic islet cells is halted, resulting in cardiovascular collapse and decreased insulin production.

Conventional treatments include massive fluid resuscitation, attempts to increase calcium inflow by infusing calcium, increasing intracellular cyclic AMP (adenosine monophosphate) by way of adenylate cyclic stimulation with either adrenalin or glucagon, or phosphodiesterase inhibition with amrinone or milrione. Pacemakers and aortic balloon pumps are other theoretical interventions but usually fail. All of these interventions are nonspecific, and not bona fide antidotes. Even a very aggressive nonspecific armamentarium, however, does not always reverse cardiovascular toxicity of severe calcium channel blocker overdose. For the suicidal patient, this can be a deadly overdose, indeed, but it wreaks havoc even on the curious toddler.

Normally, unstressed myocardial cells oxidize free fatty acids as the primary energy substrate. In the presence of cardiovascular collapse, the alternate fuel is glucose. But if glucose cannot be delivered to the myocardium and there is no circulating insulin, vascular and myocardial cells are compromised. One theory behind HIET is that blockade of the calcium channels impairs insulin release from the pancreas and impairs glucose uptake by tissues, resulting in hyperglycemia. (J Pharmacol Exp Ther 1993;264[1]:35). Hyperglycemia is a common but little publicized feature of calcium channel blocker poisoning so hypoinsulinemia and insulin resistance may be true cornerstones in the pathophysiology of calcium channel blocker cardiovascular toxicity, and may be as important as the direct effects of cellular calcium channel blockade. Providing insulin and glucose may be the key to the reversal of calcium channel blocker toxicity.

The actual regimen of HIET is somewhat varied, and has not been prospectively validated. It appears that small doses of insulin are not effective. This is no time to be timid and conger up physiologic insulin drips used for diabetic ketoacidosis. The authors suggest administering regular insulin at 1 unit/kg IV bolus, followed by 0.5 units/kg/hr, and titrating upward. Infusion of insulin at 1 unit/kg/hr is not an uncommon suggestion in the case reports cited in these articles. In addition to continuous infusion of high-dose insulin, HIET includes frequent blood glucose monitoring by fingerstick testing to minimize hypoglycemia. Maintaining euglycemia may require up to 10 to 30 grams of glucose per hour, usually delivered as a 10% infusion, with attention to potential hypokalemia.

These authors take the rather bold but not unprecedented stance of suggesting that instead of using HIET for rescue therapy, this concoction may be used early because it may be the more scientific approach. Side effects are few, the technique is widely available and relatively inexpensive, and failures seem to be related to late rather than early use of this intervention previously considered only as rescue therapy.

While some clinicians also suggest HIET for beta blocker overdose, these authors are more cautious by admitting that experience is lacking, and do not yet recommend it with such gusto for reversing beta blocker toxicity.

In the article and commentary, the authors summarize the extant animal experiments and clinical observations that seem to confirm that HIET is able to improve inotropy and increase peripheral vascular resistance, reverse metabolic acidosis, and increase survival in severe calcium channel blocker overdose. (See also Crit Care Med 1995;23[7]:1251 and J Toxicol Clin Tox 1999;37[4]:463). Importantly, the effects are not immediate, and it may require 30 to 45 minutes before one sees progress, hence the caveat to use it early before other more common interventions have totally failed, and the process is irreversible.

Some patients with hypotension, bradycardia, and heart block who were resistant to standard therapy responded quite dramatically to HIET, and the authors concluded that this therapy is theoretically and clinically supported as initial, not only rescue, adjunctive therapy.

The predominant adverse affects are the obvious hypoglycemia and the potential for hypokalemia. Because calcium channel blocker overdose produces hyperglycemia itself, the use of supplemental glucose is somewhat of an enigma, and some patients do not require significant glucose supplementation. Even in the face of a rather gargantuan insulin infusion, the use of supplemental glucose should be individualized, and no set protocol yet exists.

If one recalls the treatment of hyperkalemia as including glucose/insulin therapy, the development of hypokalemia is not a puzzling potential side effect of HIET. Potassium supplementation is not always required, however. Potassium levels should be monitored and treated accordingly. The duration HIET therapy is guided by clinical response, most notably hemodynamic parameters.

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Heart block and heart rate may not be affected by HIET, even though cardiac output increases. The clinical toxicity of the beta blocker overdose is somewhat similar to a calcium channel blocker overdose, and you can't differentiate these toxins at the bedside. In fact, traditional initial therapies are similar for both ingestions. Intentional overdoses are often mixed intoxications, and patients frequently take both beta blockers and calcium channel blockers.

Comment: The reluctance to administer an unconventional, almost bizarre, nonintuitive therapy that includes enormous doses of IV insulin to a very unstable patient can be appreciated, but HIET has been on the toxicologist's antidote plate for more than a decade. (Crit Care Med 1995;23[7]: 1251.) It continues to survive as a cult toxicologist's secret. (N Engl J Med 2001;344[22]:1721.) To my assessment, HIET falls under the same category as lipid emulsion therapy for emergency physicians. While receiving taciturn approval by the gusty toxicologist, reticence and clinical caveats exist for the EP faced with a crashing patient, often one without a specific diagnosis. HIET appears to be safe, is supported by anecdotal experience, and has few downsides. The vagaries of HIET are fully known. Importantly, however, both lipid emulsion and HIET seem to offer at least something extra for soon-to-die patients.

Our toxicology service has had personal experience with HIET in a few dozen calcium channel blocker overdoses, and has gleaned mixed results, but toxicologists are often consulted just prior to or during cardiac arrest. My advice: If you are doing CPR, call the chaplain, not the pharmacy to make up an insulin drip. HIET is a routine phone suggestion by our toxicology fellows, but colleague acceptance is mixed. This article and editorial are an easy read, and they nicely outline current thinking. They probably embody the current knowledge base on this subject. I applaud the authors for their aggressive approach, although their enthusiasm and ebullience is not ubiquitous. There is no standard of care that currently mandates that this therapy be started in the ED. Obviously other standard therapies should not be eschewed by the clinician eager to be the first on the block with this still-novel pseudoantidote.

Anything is easier to treat when the diagnosis is known. But in real emergency medicine life, it's not that simple. One is routinely bombarded with hemodynamic disasters and little or no history, let alone have EMS be cognizant of the culprit's brand name. A depressed 30-year-old man with a pill bottle and suicide note in hand is not a total clinical enigma, but the last calcium channel blocker disaster I saw was a 75-year-old man thought to have sepsis for the first few hours.

The list of entities mimicking calcium channel blocker overdoses is huge, including primary heart disease, a cornucopia of non-toxins, and a passel of cardiovascular insults, peppered with the occasional Lyme disease, hypothryoidism, and hypothermia. Basic emergency medicine will consume all your efforts for the first 60 minutes, but then one must regroup and consider the whole gamut of potential suspects, and perhaps consider more exotic interventions.

There is no way to confirm calcium channel blocker or beta blocker overdose in the ED. One tipoff to calcium channel blocker overdose, one that has been long recognized but not commonly appreciated, is hyperglycemia. (J Am Coll Cardiol 1983; 2[6]:1228.) Finding a glucose level of 280 mg/dL in an otherwise healthy nondiabetic 30-year-old with hypotension and bradycardia might cause the stellar diagnostician in search of the save-of-the-month to consider calcium channel blocker toxicity. That would impress anyone because most would dismiss minor hyperglycemia as a stress or prehospital dextrose reaction.

Those of us who have lived through quickly fading medical miracles and a plethora of seemingly reasonable and stunning case reports might label impressive claims for this fancy-schmancy potion as familiar territory. Unfortunately, HIET for calcium channel blocker toxicity is unlikely to be the object of multicenter, funded, prospective clinical trials. I found it important that Goldfranks' Toxicologic Emergencies (8th edition, New York: McGraw Hill; 2006) concludes that “the most promising treatment for patients who are severely poisoned with CCBs may be hyperinsulinemia/euglycemia therapy” and “early institution of HIET is recommended.” I think it will be the toxicologists and EPs in the trenches at 3:00 a.m. who will ferret out this topic. So far, the possible empiric interventions for the dying overdose patient that probably can't hurt, and just might help, are HIET and lipid emulsion infusion. Why not consider both early on?

I don't think there is a doctor in the world who can save the life of a patient who has overdosed on massive calcium channel blockers or beta blockers. Decompensation can be exceedingly rapid, often occurring without warning, minutes after you prognosticated a seemingly benign overdose. Calcium channel blockers and beta blockers are just too toxic to the heart and vascular system to be reversed by mere mortals.

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Proposed Experimental Hyperinsulinemia-Euglycemia Therapy (HIET) Protocol for Calcium Channel Blocker Overdose

Regular insulin: 1 unit/kg IV bolus, followed by 0.5-1 unit/kg/hr infusion. Smaller doses of insulin, such as those used for DKA, are not suggested.

Glucose: Check fingerstick glucose every 30 minutes, and supplement glucose as required. Potential glucose requirement is 15 g/hr to 30 g/hr in an adult. (Empirically start an infusion of 10% glucose at 100 ml/hr, equivalent to 10 g/hr, and adjust as needed.) Glucose requirements vary, and calcium channel blocker overdose itself can cause hyperglycemia. Not all cases require large glucose supplementation. One ampule of 50 ml of 50% glucose contains 25 grams of glucose.

Potassium: Because insulin-glucose may lower serum potassium, check potassium regularly, and adjust potassium supplementation as needed to maintain normokalemia.

Caveats

* Not FDA approved, but few downsides.

* Institute early for treating serious cardiovascular compromise.

* Use concomitant standard therapy (fluids, vasopressors, calcium, glucagon, inotropic agents).

* HIET may not be effective for 30 to 60 minutes.

* Although cardiac output and blood pressure may increase, bradycardia and heart block may be resistant.

* Titrate to effect and clinical improvement; maximum dose/duration is unknown.

Sources: Crit Care 2006;10(3):212; N Engl J Med 2001;344[22]:1721; Ann Pharmacother 2005;39[5]:923; Crit Care 2006;10(4):149.

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CME Participation Instructions

To earn CME credit, you must read the article in Emergency Medicine News, and complete the evaluation questions and quiz, answering at least 80 percent of the questions correctly. Mail the completed quiz with your check for $12 payable to Lippincott Continuing Medical Education Institute, 530 Walnut Street, 8th Floor East, Philadelphia, PA 19106. Only the first entry will be considered for credit, and must be received by Lippincott Continuing Medical Education Institute by January 31, 2011. Acknowledgment will be sent to you within six to eight weeks of participation.

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