Are We Ready to Utilize Insulin-Glucose as Routine Therapy for Calcium Channel Blocker Toxicity?
Russ Kerns, MD
Carolinas Medical Center
Int J Med Toxicol 1998; 1(5): 23
The immediate answer to this question is no: Any novel antidote that results from animal experimental work should not make the leap to routine use without clinical evaluation. However, this novel treatment for calcium channel blocker (CCB) toxicity is poised for formal testing in the clinical arena.
Severe CCB toxicity remains a challenge to most physicians. Standard treatment modalities such as calcium, catecholamines, glucagon, and pacing often fail to improve myocardial function and hemodynamics in these severe cases. At least 44 deaths occurred nation wide in 1997.(1) Of all cardiovascular agents in the 1997 database, CCBs had the highest absolute number of fatalities. Reported CCB deaths are most commonly associated with the phenylalkylamine class, namely verapamil.
Most CCBs antagonize L-type calcium channel mediated calcium entry into cardiomyocytes and smooth muscle that is necessary for contractile function and electrical conduction. Predictably, overdose is characterized by decreased myocardial function and peripheral vasodilation that produces a state of hypodynamic shock with hallmark bradycardia, conduction blocks, and systemic hypotension.(2)
Interestingly, CCB intoxication is associated with hyperglycemia and lactic acidosis, metabolic derangements similar to diabetic ketoacidosis.(3) Recent investigations attribute the diabetic ketoacidosis-like findings to defective carbohydrate catabolism during shock. (4,5)
Altered carbohydrate catabolism may contribute to a vicious cycle of hypodynamic shock during CCB toxicity. In the unstressed, aerobic state, the myocardium relies primarily on oxidation of free fatty acids for mechanical energy. During CCB induced shock, substrate preference shifts from free fatty acids to carbohydrates.(5) However, CCBs prevent adequate myocardial utilization of carbohydrates, due to several synergistic mechanisms. First, there is a lack of available insulin due to inhibition of calcium mediated insulin release by pancreatic islet cells.(6) Second, during toxicity there is insulin resistance.(4) Third, there is poor insulin and substrate delivery due to poor cardiac output. Hyperglycemia and poor contractility result.
Lactic acidosis is also a common manifestation of CCB toxicity. This may be due to mitochondrial pyruvate dehydrogenase inhibition. Calcium is required for mitochondrial pyruvate dehydrogenase activation in-vivo. In high concentrations, CCBs inhibit mitochondrial calcium entry, which in turn can decrease pyruvate dehydrogenase activity.(7) As a result, pyruvate cannot enter the Krebs cycle and lactate accumulates, producing metabolic acidosis.
The rationale behind the use of insulin to treat CCB-induced shock is based on insulin’s positive inotropic property. This effect has been recognized for several years.(8) The inotropy is especially evident in the setting of myocardial depression. For example, insulin improves contractility in anoxic, isolated rat hearts.(9) Following beta blockade with practolol, insulin also increases the rate of developed pressure in piglet hearts compared to glucagon.(10) More recently in humans, insulin and glucose treatment improved cardiac index following cardio-pulmonary bypass surgery.(11) Insulin and glucose increased survival after acute myocardial infarction.(12)
Specifically for CCB-induced shock, animal studies and initial human series employing insulin-euglycemia are very promising and allow new insight into the toxic mechanism.
Anesthetized canines were surgically instrumented for multiple cardiodynamic and hemodynamic measures, prior to receiving continuous verapamil infusion. All animals developed characteristic toxicity including bradycardia with atrioventricular dissociation, depressed contractility, and systemic hypotension. Animals then received sham, epinephrine, glucagon, or insulin-euglycemia treatment. After four hours of treatment, all animals in the insulin-euglycemia group survived, compared to zero sham animals, four epinephrine animals, and three glucagon animals. At the end of four hours, all remaining animals received a verapamil bolus. Only the insulin treated group survived the additional drug insult. The significant survival effects were related to improved contractility and increased tissue perfusion.(13) Further study using awake canines that received intraportal verapamil revealed similar results; insulin improved survival compared to epinephrine, glucagon, or calcium.(5) An additional study found that negative inotropy during verapamil toxicity was related not only to myocardial calcium channel inhibition, but also to the inability of the myocardium to utilize carbohydrates during shock.(14)
It appears that the treatment effect of insulin-euglycemia rests in the ability to promote adaptation to myocardial metabolic changes during drug induced shock, i.e. the switch from fatty acid to carbohydrate oxidation. In verapamil toxic canines, insulin-euglycemia increased carbohydrate uptake and oxidation.(5,15) Enhanced carbohydrate oxidation was associated with increased myocardial mechanical performance (contractility, left ventricular pressure, and rate of developed pressure). Better mechanical performance occurred without increasing work as evidenced by an increased ratio of oxygen delivery to oxygen uptake. On the other hand, standard treatments like epinephrine and glucagon enhanced fatty acid oxidation with only transient increases in contractility. This occurred at the expense of increased myocardial oxygen consumption. Therefore, insulin provides the environment for more efficient myocardial metabolism during shock compared to standard antidotes.
Pilot Human Cases
In an uncontrolled small case series reported at the 1997 North American Congress of Clinical Toxicology, insulin-euglycemia was successfully used as rescue treatment for patients with severe CCB toxicity.(16) The series involved 4 patients with isolated verapamil overdoses and one patient with combined amlodipine and atenolol overdose. All patients had hypotension; four had bradycardia with third degree atrioventricular block; four developed coma, and four had evidence of acidemia. When hypotension and bradycardia did not respond or failed to maintain a consistent response to conventional therapy, the treating physicians entertained the use of insulin-euglycemia. In all cases, the physicians were concerned that the patients were on the verge of developing irreversible shock with impending death. Because insulin-euglycemia is experimental, attempts were made to discuss the use of this treatment with family. Four families agreed and, in one case, no family was available. All five patients survived. The main effect of insulin appeared to be hemodynamic and cardiodynamic. Blood pressure normalized in all five. In one patient, a pre- and post-insulin echocardiogram noted an increase in ejection fraction from 10 to 50%. Interestingly, insulin had little effect on heart rate.
The mean insulin dose was 0.5 units/kg/hr (range 0.1-1.0 units/kg/hr). Relatively large doses of insulin were used, consistent with doses used in published animal studies and because of insulin resistance that occurs with CCB-induced shock. The mean duration of insulin infusion was 25.9 hr (range 7.5-48 hr). The mean exogenous glucose requirement in these patients was 23.1 gm/hr (range 5-75 gm/hr).
There were two potential adverse events (numeric hypoglycemia in two intubated patients, one event each) during insulin usage. However, bedside glucose testing was being performed frequently and euglycemia was rapidly restored. CCB and beta blocker presence was confirmed by blood levels in all cases.
Aside from animal and pilot clinical data, insulin has additional potential benefits compared to standard therapies. Insulin is more readily available than glucagon. In a survey of 47 metropolitan hospitals, 0 % of emergency departments and only 26 % of hospital pharmacies stocked sufficient glucagon to treat for one hour.(17) Insulin is less costly. Comparing roughly equivalent doses (5 mg/hr glucagon vs. 1 unit/kg/hr insulin), glucagon costs the pharmacy $150, while insulin costs $0.63 plus minimal charges for glucose (author’s hospital data). Assuming careful glucose monitoring, insulin has fewer potential adverse effects than conventional agents. Glucagon produces nausea and vomiting, an undesirable event in patients with altered mental status.(2) Catecholamines and calcium chloride may cause dysrhythmias, increased myocardial oxygen demand, and tissue necrosis.(2,18)
Taken together, the laboratory investigations and pilot series compelled our group of investigators to organize an experimental treatment algorithm for severe CCB toxicity that incorporates the use of insulin and glucose. The experimental protocol has been approved by the institutional human research oversight committee (author’s hospital). However, CCB toxicity is relatively uncommon for any one treatment facility. For example, the referenced case series took place over 16 months. Thus, in order to complete a prospective evaluation in a timely fashion, the study will need to be multi center. Several centers have expressed interest in participating. Currently, investigators are seeking adequate funding to perform such a multi center study.
Globally, this is the direction needed for evaluation of novel toxicology treatments. No one center will likely evaluate enough patients to make valid and timely observations or efficacy conclusions. It requires collegial cooperation from multiple centers. Several research groups, such as the Antidepressant Study Group and the META (fomepizole) Study Group, have worked well. Their studies are beginning to appear in the toxicology literature. Without a group effort, these works would not come to fruition for several additional years.
Russ Kerns, MD
Department of Emergency Medicine
Carolinas Medical Center
PO Box 32861
Charlotte, NC 28232
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Int J Med Toxicol 1998; 1(5): 23
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