High-Dose Insulin Therapy for Calcium-Channel Blocker Overdose

RECENT ADVANCES Toxicology and Poison Control

High-Dose Insulin Therapy for Calcium-Channel Blocker Overdose Greene Shepherd and Wendy Klein-Schwartz

OBJECTIVE: To evaluate the evidence for using high-dose insulin therapy with supplemental dextrose and potassium in calciumchannel blocker (CCB) overdose. DATA SOURCES:

Evidence of efficacy for high-dose insulin therapy with supplemental dextrose and potassium was sought by performing a search of MEDLINE and Toxline between 1966 and July 2004 using combinations of the terms calcium-channel blocker, overdose, poisoning, antidote, and insulin. Abstracts from the North American Congress of Clinical Toxicology for the years 1996–2003 were also reviewed.

STUDY SELECTION AND DATA EXTRACTION: Identified articles, including animal studies, case reports, and case series, were evaluated for this review. No clinical trials were available. DATA SYNTHESIS:

Animal models of CCB overdose demonstrate that high-dose insulin with supplemental dextrose and potassium was a more effective therapy than calcium, glucagon, or catecholamines. High-dose insulin appears to enhance cardiac carbohydrate metabolism and has direct inotropic effects. Published clinical experience is limited to 13 case reports where insulin was used after other therapies were failing; 12 of these patients survived. High-dose insulin therapy was beneficial for CCB-induced hypotension, hyperglycemia, and metabolic acidosis. Bradycardia and heart block resolved in some patients, but persisted in others.

CONCLUSIONS: Based on animal data and limited human experience, as well as the inadequacies of available alternatives for patients with significant poisoning, high-dose insulin therapy warrants further study and judicious use in patients with life-threatening CCB poisoning. KEY WORDS: calcium-channel blocker overdose, insulin.

Ann Pharmacother 2005;39:923-30. Published Online, 5 Apr 2005, www.theannals.com, DOI 10.1345/aph.1E436 THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREDIT

alcium-channel blocker (CCB) overdoses may be the C result of unintentional ingestions by children or intentional overdoses by suicidal adults. Other reasons for intoxications include medication errors (eg, double dosing) or adverse effects. Interactions with drugs that affect cardiac

Author information provided at the end of the text. Approved for publication by the Toxicology and Poison Control Panel.

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conduction or inotropy or that inhibit CYP3A isoenzymes involved in the metabolism of CCBs may also be involved.1 CCB overdose is associated with significant morbidity and mortality. In 2002, the American Association of Poison Control Centers Toxic Exposure Surveillance System (TESS) reported 9650 CCB exposures, 50% of which were treated in healthcare facilities.2 Outcomes, where known, according to standard TESS criteria were moderate toxicity (pronounced or prolonged adverse clinical effect) in 1142 cases, major toxicity (permanent or life-threaten-

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G Shepherd and W Klein-Schwartz

ing adverse clinical effect) in 339 cases, and death in 57 cases. Verapamil is the CCB most frequently implicated in fatalities, followed by diltiazem, amlodipine, nifedipine, and felodipine. Minimally invasive treatments for CCB overdoses that are consistently effective are needed. Recent evidence suggests that high-dose insulin (0.5–1 units/kg), with supplemental dextrose and potassium (HDIDK) as needed, may be an effective therapy. Data Sources Evidence of insulin’s use in animal models and clinical use in patients with CCB overdose was sought by performing a search of MEDLINE and Toxline between 1966 and July 2004 using combinations of the medical subject heading terms calcium-channel blocker, overdose, poisoning, antidote, and insulin. Abstracts from the North American Congress of Clinical Toxicology for the years 1996–2003

were also reviewed. This paper reviews CCB toxicity in overdose and its treatment, with a focus on the use of HDIDK. Mechanisms of Calcium-Channel Blocker Toxicity in Overdose CCBs antagonize calcium channels in myocardial cells, smooth muscle, and β-islet cells of the pancreas.2 CCB poisoning causes toxicity in the myocardium by 2 mechanisms (Figure 1). First, by preventing calcium entry through voltage-sensitive channels, CCBs impair conduction and muscle contraction. Second, by inducing insulin resistance, which causes serum glucose levels to rise while intracellular stores fall, this drug class causes the cell to switch to inefficient fatty acid metabolism to make energy. Negative inotropic effects result from channel blockade in cardiac muscle, while negative chronotropic and dro-

Figure 1. Proposed sites of action in cardiac muscle for calcium-channel blocker therapies. 1 Administration of exogenous calcium competitively overcomes blockade of voltage-sensitive calcium channels to enter the cell and promote release of sarcoplasmic calcium stores. The sarcoplasmic calcium combines with troponin to cause contraction via actin and myosin fibers. 2 Epinephrine (EPI) binds to β-receptors coupled to a G-protein that activates AC to convert adenosine triphosphatase (ATP) into cyclic adenosine monophosphate (cAMP). 3 Glucagon bypasses the β-receptor and acts directly on the G-protein that activates AD to convert ATP into cAMP. 4 Amrinone inhibits phosphodiesterase (PDE) to prevent the degradation of cAMP. cAMP activates protein kinase A (PKA), which promotes opening of dormant calcium channels, enhances release of scarcoplasmic calcium, and facilitates release of calcium by troponin during diastole. Therapies that promote cAMP generally have transient effects due to the myocyte running out of carbohydrates. 5 Insulin administration promotes the uptake and utilization of carbohydrates as an energy source. It also promotes antiinflammatory effects that may correct problems caused by inefficient energy production. The associated influx of potassium may also provide benefit by prolonging repolarization and allowing calcium channels to remain open longer.

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Insulin for Calcium-Channel Blocker Overdose

motropic effects are due to blocking channels in the sinoatrial (SA) and atrioventricular (AV) nodes, respectively. As a result of channel blockade in vascular smooth muscle, afterload and systemic blood pressure decrease and coronary vascular dilation increases. CCBs exhibit different selectivity for cardiac versus vascular channels.1 Selectivity may relate in part to whether the drug binds to the channel preferentially in the open state or in both the open and closed states and the affinity of the drug for cardiac versus central α1-subunits of the L-type channel. Dihydropyridines, such as amlodipine and nifedipine, act predominantly on peripheral vasculature, while verapamil and diltiazem are less selective, exhibiting direct cardiac effects as well as peripheral vascular activity. Because dihydropyridines decrease peripheral resistance and increase coronary artery blood flow, reflex tachycardia is common. Verapamil and, to a lesser extent, diltiazem depress SA and AV nodal conduction, decrease myocardial contractility, and decrease peripheral vascular resistance. In an overdose, pharmacologic distinctions between different CCBs may not be clinically evident; therefore, treatment for cardiovascular effects should be similar regardless of which agent is involved. Cardiotoxicity evident in overdose results from exaggeration of normal pharmacology and decreased cardiac carbohydrate metabolism.3 Hyperglycemia results from decreased insulin release due to blocked calcium influx into pancreatic islet cells. Hypoinsulinemia contributes to impaired cardiac function and shock by preventing glucose uptake and utilization by myocytes.4 This is similar to other causes of shock and results in negative inotropy and a drop in peripheral vascular resistance. Metabolic acidosis develops systemically due to the resulting decrease in tissue perfusion. Negative inotropy during verapamil toxicity is theorized to be related to the inability of the myocardium to utilize carbohydrates during shock, as well as myocardial calcium-channel inhibition. Clinical Manifestations of Calcium-Channel Blocker Overdose and Current Therapies Clinically, CCB overdose is characterized by cardiovascular toxicity,1 with hypotension and conduction disturbances, including sinus bradycardia and varying degrees of AV block. Hypotension results from vasodilation, decreased myocardial contractility, and decreased cardiac output related to negative chronotropic and inotropic effects. Central nervous system effects include drowsiness, confusion, agitation, and seizures. Other manifestations include pulmonary edema (cardiac and noncardiogenic), hyperglycemia, and metabolic acidosis. Terminal events include cardiogenic shock and cardiac arrest. Controlled-release or extendedrelease CCB preparations have the potential for prolonged toxicity after ingestion of only a few tablets. Crushing or chewing these preparations may deliver the entire dose all at once. Patients with life-threatening intoxication require multiple therapeutic interventions that achieve varying degrees of success, dependent to some extent on the amount ingestwww.theannals.com

ed and the patient’s underlying medical conditions. In addition to supportive care, gastrointestinal decontamination, and fluid resuscitation, there are several potential therapies for CCB overdose. Traditionally, these have included atropine, calcium, glucagon, adrenergic drugs (dopamine, norepinephrine, epinephrine), amrinone, and mechanical supportive measures such as transvenous pacing, balloon pump, and extracorporeal bypass.1 In severely intoxicated patients with life-threatening clinical effects, use of these agents does not consistently improve hemodynamic parameters or ensure survival. Calcium, usually the first drug for the treatment of hypotension and conduction disturbances (Figure 1) from CCB overdose, produces variable results. There are many reports of no effect or inadequate response with calcium, although inadequate doses may contribute to its apparent lack of efficacy in life-threatening overdoses.2 Atropine is usually the first-line agent for symptomatic bradycardia, but its mechanism yields poor response in moderate to severe CCB overdose.3 Following calcium administration, atropine may reverse bradyarrhythmias associated with hypotension in mildly intoxicated patients.5 Glucagon appears to have positive inotropic, chronotropic, and dromotropic effects in patients with CCB overdose (Figure 1).1 However, a review of animal models of CCB poisoning treated with glucagon indicates that it does not improve survival.6 Case reports show mixed results on hemodynamic parameters and survival after glucagon administration, although in some instances the glucagon dose may have been inadequate.1,6 As of March 19, 2005, there have been no controlled human studies of glucagon use in CCB overdose.6 Amrinone reverses myocardial depression inhibiting phosphodiesterase (Figure 1), but it may worsen hypotension; human experience in CCB overdose is limited.1 Catecholamines increase blood pressure and heart rate but also increase myocardial oxygen demand, which may compromise cardiac function (Figure 1). Recent research in dogs with verapamil poisoning suggests that HDIDK is more effective at improving survival compared with calcium, glucagon, or catecholamines.3,4,7-9 Rationale for Insulin-Based Therapy The use of HDIDK is not a new concept.10 Insulin-based therapies to support cardiac function have been examined in several patient populations. These therapies appear to be beneficial when cardiac dysfunction is accompanied by acute hyperglycemia and resultant inflammatory processes. Acute myocardial infarction, cardiac surgery, endotoxin-mediated septic shock and, more recently, CCB overdose have been evaluated.11-15 Insulin promotes cellular uptake of glucose in muscle and adipose tissue. Additionally, it reduces cytosolic calcium concentration by activating sodium–potassium pumps linked to the generation of adenosine triphosphatase (ATP). This uptake process increases movement of potassium into the intracellular space, resulting in lower extracellular potassium concentrations. In the setting of ischemic heart failure,


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cardiac function can be further improved by using HDIDK in addition to therapies geared toward increasing myocardial blood flow and tissue oxygenation. Insulin and dextrose promote inotropy by stimulating myocardial energy production via activating calcium and potassium channels to regenerate cytosolic ATP and promoting aerobic metabolism.15 Animal studies have demonstrated that simply administering dextrose in the absence of insulin is not beneficial and that insulin is the essential component.12 In fact, hyperglycemic states are known to enhance ketosis, inflammatory activity, and free radical (superoxide) formation. This is thought to be related to increased oxidation of free fatty acids because carbohydrates are not available intracellularly. Beyond simply controlling blood glucose, insulin appears to exert cardioprotective effects by inhibiting inflammatory processes in a variety of models. Insulin suppresses tumor necrosis factor α, interleukin-6, proinflammatory cytokines, and free radical production. At the same time, it promotes antiinflammatory activity, through the release of nitric oxide and interleukins 4 and 10. By these mechanisms, insulin appears to protect against apoptosis, as well as ischemic and reperfusion injury associated with shock.12 Animal Studies of HDIDK Therapy Evidence supporting HDIDK therapy in CCB overdose has increased over the past few years, and its use is becoming more common. There are several studies using verapamil in a canine model that indicate that HDIDK is likely to be an effective therapy through enhanced cardiac carbohydrate metabolism and direct inotropic effects. The canine model is useful in that it provides a vertebrate with a 4-chambered heart and is large enough that instrumentation and blood sampling can be easily performed. Twenty-four dogs randomized to receive NaCl 0.9% (saline) at 2 mL/min (control group), epinephrine 1 µg/kg/ min, glucagon 0.2–0.25 µg/kg bolus then 150 µg/kg/h, or HDIDK 4 units/min were anesthetized, and cardiovascular monitoring instruments were placed prior to administration of continuous verapamil infusion at 0.1 mg/kg/min.7 Within 30 minutes, all animals developed characteristic toxicity and treatments were started. After 4 hours of treatment, all 6 dogs in the HDIDK group survived, compared with 4 of 6 of those in the epinephrine group, 3 of 6 in the glucagon group, and none of the 6 controls. During treatment, the HDIDK group did not demonstrate increases in heart rate or mean arterial pressure but did have increased survival, which could be correlated with improvements in cardiac efficiency and output. All surviving animals then received a 3-mg/kg verapamil bolus. Only the 6 dogs in the insulin group survived the additional drug insult, and survival was attributed to improved contractility and increased tissue perfusion. Another study by the same group added a calcium (intravenous CaCl 20 mg/kg then 0.6 mg/kg/h) treatment group and pooled it with data from the previous study to evaluate the effect of treatments on carbohydrate metabolism.9 HDIDK improved survival compared with calcium 926

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at 4 hours (6 of 6 HDIDK vs 3 of 6 CaCl) and after a 3mg/kg verapamil bolus (6 of 6 HDIDK vs 0 of 6 CaCl). Ratios of myocardial oxygen delivery to work were evaluated for evidence of improvement in this study. The investigators found that improvements in this ratio correlated with increases in carbohydrate uptake by cardiac muscle from all therapies. Only the insulin group was able to maintain these improvements. Another study found that HDIDK was well tolerated in 6 healthy dogs at rates as high as 1 unit/min.8 Similar results were found in 12 awake dogs that received intraportal verapamil to better simulate an oral overdose; HDIDK 1 unit/min improved survival compared with saline as a control.8 An additional study of 20 dogs given intraportal verapamil infusions found that, among HDIDK (1 unit/min), epinephrine (5–10 µg/kg/min), or glucagon (0.2-µg/kg bolus then 10 µg/kg/min) treatments versus saline control (3 mL/kg/min), only insulin significantly (p < 0.05) increased the lethal dose (HDIDK 85 mg/kg vs saline 43 mg/kg) and delayed time to death the longest (HDIDK 360 min, epinephrine 125 min, glucagon 208 min, saline 149 min).3 This study monitored myocardial carbohydrate, fatty acid and oxygen uptake, and ventricular function. The negative inotropy observed during verapamil toxicity in this study correlated with the inability of the myocardium to utilize carbohydrates. The administration of insulin improved uptake and correlated with improved function. Epinephrine and glucagon promoted increased fatty acid utilization, which decreased mechanical efficiency compared with saline and insulin. The studies described above suggest that the beneficial effect of HDIDK on verapamil-induced cardiotoxicity in dogs is found in the promotion of carbohydrate metabolism during verapamil-induced shock rather than direct effects on the calcium channel. In verapamil-toxic dogs, insulin appears to stimulate more efficient myocardial carbohydrate metabolism during shock compared with standard therapies. HDIDK increased carbohydrate uptake and oxidation for sustainable benefits, while glucagon or epinephrine enhanced fatty acid metabolism, which promotes ketosis and results in only transient benefits.3,9 Clinical Experience with HDIDK Infusions Based on improved survival in animal studies, HDIDK therapy has recently been used in humans for the treatment of CCB overdose. Published human experience consists of 13 cases (Table 1).16-23 In evaluating the efficacy of HDIDK therapy based on these 13 patients, important limitations should be considered including the history of coingestants in 4 cases, the lack of standardization of the dosing regimen, and the fact that, in all instances, patients had already received and continued to receive other therapies. In many cases, HDIDK was considered as rescue treatment for shock refractory to other interventions. As of March 19, 2005, there are no data on the use of HDIDK as a first-line therapy. There is also the possibility of underreporting of negative findings due to publication bias so that some cas-

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es in which patients died or did not respond to HDIDK were either not submitted or not accepted for publication. Insulin bolus doses and infusion rates varied among the reported cases. Six patients received bolus insulin doses of 10–20 units and a seventh patient, who was supposed to re-

ceive 1 unit/kg, inadvertently received 10 units/kg (1000 units). Infusion rates ranged from 0.1 to 1 unit/kg/h. Clinical improvement usually occurred within 20– 45 minutes after initiation of insulin therapy. Duration of therapy varied from a single bolus dose to infusions for 5– 6 hours to as

Table 1. Clinical Experience with High-Dose Insulin Infusions

Reference Boyer et al. (2001)16

CCB (co-ingested drugs)

Age (y) 34

Dose of CCB

Insulin Dose

Response to Insulin/ Dextrose

Duration of Insulin Therapy (h)

Therapies Prior to HDIDK

Outcomea

amlodipine

0.86 mg/kg (30 mg total)

0.5 units/kg/h

hypotension resolved

6

AC, dopamine, dobutamine, NE, glucagon

survived

Rasmussen 36 et al. (2003)22

amlodipine (clonazepam, citalopram, acetaminophen)

280 mg

20-unit bolus for hyperkalemia (6.5 mEq/L)

hypotension resolved; thirddegree block converted to NSR

1 bolus dose

AC, furosemide, dopamine, phenylephrine, calcium, epinephrine

survived

Yuan et al. (1999)23

37

amlodipine (atenolol, alprazolam)

6.7 mg/kg

unspecified n of 20-unit boluses, then variable rate infusion; highest dose 0.5 units/kg/h


49

lavage, AC, dopamine, dobutamine, intubation, NE, atropine, glucagon, calcium

survived

Boyer et al. (2001)16

48

diltiazem ER

unknown

0.5 units/kg/h


5–6

calcium, dopamine, dobutamine

survived

Marques et al. (2003)18

75

diltiazem (indapaunknown mine, benzodiazepines, cetirizine, diclofenac, celecoxib, digoxin, diosmin, trimetazidine)

0.5 units/kg/h

hypotension resolved; ventricular response to atrial fibrillation (chronic) increased from 35–50 to 80 beats/ min

17

lavage, AC, atropine, calcium, intubation/ventilator, dobutamine, NE, glucagon

survived

Morris-Kukoski 5 nifedipine et al. (2000)20 mo

20 mg

1 unit/kg/h


96

intubation/ventilation, calcium, glucagon, dopamine, epinephrine, phenylephrine, milrinone

survived

Meyer et al. (2003)19

13

verapamil SR

3.0–3.6 g

0.1 unit/kg/h


26

lavage, AC/cathartic, intubation, calcium, glucagon, NE, epinephrine

survived


14

verapamil SR

30 mg/kg over 10 units, then 12 6h units/h; then 20 units/h (highest dose 0.5 units/ kg/h)


9

calcium, atropine, AC

survived

31

verapamil SR

71 mg/kg

10 units; then 4 hypotension resolved; units/h; within 2 h, HR increased; thirdincreased to 8 degree block conunits/h; 2 h later, verted to NSR increased to 10 units/h; highest dose 0.1 unit/kg/h

18

AC, calcium, glucagon, atropine

survived

36

verapamil SR

53 mg/kg

10 units; then 30 units/h; highest insulin dose 0.3 units/kg/h


33

AC, whole bowel irrigation, calcium, glucagon, intubation/ventilator

survived

49

verapamil SR

192 mg/kg

1000-unit bolus

hypotension resolved; improved cardiac output and stroke volume

1 bolus dose

dopamine, pacemaker, calcium, glucagon, NE

survived

Place et al. (2000)21

AC = activated charcoal; CCB = calcium-channel blocker; ER = extended release; HDIDK = high-dose insulin with supplemental dextrose and potassium; NE = norepinephrine; SR = sustained release; NSR = normal sinus rhythm. a Survived without sequelae. (continued on page 928)

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long as 96 hours.20,24 In one series of 5 patients, the mean duration of insulin infusion was 27 hours, with a range of 9– 49 hours.23 In 12 of the 13 cases, HDIDK was considered beneficial, with temporally related complete resolution of hypotension previously refractory to other therapies. In 5 cases, vasopressors were discontinued within 30 minutes to several hours after initiation of HDIDK therapy, and authors attributed discontinuation to HDIDK. Bradycardia and heart block responded in some patients, but persisted in others.17,22,23 Twelve patients survived, and surviving patients were ultimately either transferred to a psychiatric unit or discharged from the hospital without sequelae. The thirteenth patient was a 58-year-old man with a history of cardiac disease who denied self-poisoning on presentation to a hospital; however, an unspecified number of hours into his treatment, verapamil overdose was suspected.17 It was not until the second hospital day that the overdose was confirmed by a markedly elevated blood verapamil concentration. Multiple therapies, including HDIDK, were administered in an unspecified order without success, and the patient died. The delay in recognition of the overdose and in administration of HDIDK likely reduced its potential benefit in this case. Potential adverse effects of HDIDK include hypoglycemia, if inadequate doses of dextrose are coadministered, and hypokalemia.24 Although 10 of the 13 patients developed hyperglycemia from the CCB overdose, all but one required supplemental dextrose during HDIDK therapy. Concurrent infusion of dextrose was specified in 7 patients; as-needed bolus doses of dextrose were given to 2 patients and dextrose dosing was mentioned but not described for 3 patients. A 49-year-old patient with a verapamil overdose who was supposed to receive 1 unit/kg of insulin and continuous dextrose inadvertently received 1000 units of insulin.21 The patient never developed hypoglycemia. Hypokalemia results from intracellular potassi-

um shifts and patients generally remain asymptomatic. Hypokalemia (potassium 2.1–2.8 mEq/L) during HDIDK therapy was mentioned in only 4 patients; 3 of these patients received potassium supplementation. Guidelines and Recommendations for Use Boyer et al.16,24 have proposed guidelines for using HDIDK therapy for CCB overdose. These guidelines are based on experience in 5 cases and have not been evaluated prospectively. After inadequate response to fluid resuscitation, high-dose calcium, and vasopressors, dextrose (adults 50 mL of dextrose 50%; children 0.25 g/kg of dextrose 25%) and potassium (40 mEq orally) are administered to patients with glucose level 50 beats/min. Since adverse effects of insulin infusion include hypoglycemia and hypokalemia, the capillary glucose level is checked every 20 minutes for the first hour, then both serum potassium and capillary glucose levels are checked hourly. As signs of CCB toxicity diminish, the insulin infusion is weaned. HDIDK therapy appears beneficial in seriously intoxicated patients with CCB-induced hypotension, hyperglycemia, and acidosis. HDIDK does not consistently reverse bradycardia, heart block, and intraventricular conduction delay.24 Based on the mechanisms of HDIDK and other standard therapies (Figure 1), there may be benefit in using them in combination. Unfortunately, there are no data evaluating the synergies between HDIDK and other therapies. Given the limited clinical experience and lack of controlled clinical trials, HDIDK cannot be recommended as sole therapy or first-line therapy at this time. However, controlled clinical trials are difficult to perform in overdose

Table 1. Clinical Experience with High-Dose Insulin Infusions (continued)

Reference

Age (y)

CCB (co-ingested drugs)

Dose of CCB

Insulin Dose 20 units; then 35 units/h, then 70 units/h within 80 min; decreased to 36 units/h at 8 h; BP dropped, so increased to 46 units/h; highest insulin dose 1 unit/kg/h unknown


50

verapamil SR (hydrochlorothiazide)

55 mg/kg

Herbert et al. (2001)17

58

verapamil

unknown

Response to Insulin/ Dextrose BP improved, but bradycardia with third-degree block persisted

Duration of Insulin Therapy (h) 27.5

none; hypotension, unknown bradycardia, LBBB persisted

Therapies Prior to HDIDK

Outcomea

atropine, calcium, survived intubate, AC, glucagon

intubate/ventilator, died inotropes, calcium, glucagon, bicarbonate, pacemakerb

AC = activated charcoal; CCB = calcium-channel blocker; HDIDK = high-dose insulin with supplemental dextrose and potassium; LBBB = left bundlebranch block; SR = sustained release. a Survived without sequelae. b All therapies listed without clear time frame relative to HDIDK use.

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patients, and standardized therapies are often based on case reports and case series. Lack of clinical evidence supporting the use of other routinely used therapies (eg, glucagon) has not precluded their use. Animal studies indicate that HDIDK therapy should be considered earlier in the management of a serious CCB overdose. Published experience to date with HDIDK has been as rescue therapy for patients unresponsive to vasopressors, inotropes, atropine, calcium, and glucagon. However, animal data, as well as a lack of evidence of serious adverse effects associated with HDIDK therapy suggest that, with more experience, it may have a role earlier in the management of serious CCB overdose. Based on the animal and human data on its use, as well as the inadequacies of available alternatives for patients with significant poisoning, HDIDK therapy warrants continued use and further study in patients with life-threatening CCB overdose. Greene Shepherd PharmD, Clinical Associate Professor, College of Pharmacy, University of Georgia; Department of Emergency Medicine, Medical College of Georgia, Augusta, GA Wendy Klein-Schwartz PharmD MPH, Associate Professor, Maryland Poison Center, School of Pharmacy, University of Maryland, College Park, MD Reprints: Dr. Shepherd, Clinical Pharmacy Program, 1120 15th St., CJ-1020, Augusta, GA 30912-0004, fax 706/721-9934, jshepherd @mcg.edu

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15. Szabo Z, Hakanson E, Maros T, Svedjeholm R. High-dose glucose–insulin–potassium after cardiac surgery: a retrospective analysis of clinical safety issues. Acta Anaesthesiol Scand 2003;47:383-90. 16. Boyer EW, Shannon M. Treatment of calcium-channel–blocker intoxication with insulin infusion (letter). N Engl J Med 2001;344:1721-2. 17. Herbert J, O’Malley C, Tracey J, Dwyer R, Power M. Verapamil overdosage unresponsive to dextrose/insulin therapy (abstract). J Toxicol Clin Toxicol 2001;39:293-4. 18. Marques M, Gomes E, de Oliveira J. Treatment of calcium channel blocker intoxication with insulin infusion: case report and literature review. Resuscitation 2003;57:211-3. 19. Meyer M, Stremski E, Scanlon M. Successful resuscitation of a verapamil intoxicated child with a dextrose–insulin infusion. Clin Intensive Care 2003;14:109-13. 20. Morris-Kukoski C, Biswas A, Para M. Insulin “euglycemia” therapy for accidental nifedipine overdose (abstract). J Toxicol Clin Toxicol 2000; 38:577. 21. Place R, Carlson A, Leikin J, Hanashiro P. Hyperinsulin therapy in the treatment of verapamil overdose. J Toxicol Clin Toxicol 2000;38:576-7. 22. Rasmussen L, Husted SE, Johnsen SP. Severe intoxication after an intentional overdose of amlodipine. Acta Anaesthesiol Scand 2003;47:1038-40. 23. Yuan TH, Kerns WP 2nd, Tomaszewski CA, Ford MD, Kline JA. Insulin–glucose as adjunctive therapy for severe calcium channel antagonist poisoning. J Toxicol Clin Toxicol 1999;37:463-74. 24. Boyer EW, Duic PA, Evans A. Hyperinsulinemia/euglycemia therapy for calcium channel blocker poisoning. Pediatr Emerg Care 2002;18:36-7.

EXTRACTO OBJETIVO: Revisar las evidencias científicas sobre el uso de insulina a dosis altas con suplementos de dextrosa y potasio en casos de sobredosis de bloqueadores de canales de calcio. FUENTES DE INFORMACIÓN: Se buscaron las evidencias científicas para el uso de insulina en dosis altas con suplementos de dextrosa y potasio por medio de una búsqueda en MEDLINE y Toxline entre 1996 y julio 2004 usando una combinación de términos: bloqueadores de canales de calcio, sobredosis, envenenamiento, antídoto, e insulina. También se revisaron los extractos del Congreso Norteamericano de Toxicología Clínica entre los años 1966 y 2003. SELECCIÓN DE ESTUDIOS Y EXTRACCIÓN DE DATOS: En esta revisión, se seleccionaron los artículos identificados, incluyendo estudios en animales, descripciones de casos, y series de casos. No se encontraron estudios clínicos. RESUMEN DE DATOS: Los modelos de sobredosis de los bloqueadores de canales de calcio en animales demuestran que el uso de insulina a dosis altas con suplementos de dextrosa y potasio era más eficaz que la terapia de calcio, glucagón, o catecolaminas. Esta combinación parece realzar el metabolismo de los carbohidratos cardíacos y tiene efectos inotrópicos directos. La experiencia clínica publicada se limita a 13 casos en los que se utilizó la combinación después del fallo de otras terapias. Sobrevivieron 12 de estos pacientes. El tratamiento con dosis altas de insulina fue beneficioso para la hipotensión, hiperglucemia, y acidosis metabólica inducida por los bloqueadores de canales de calcio. La bradicardia y el bloqueo cardíaco se resolvieron en algunos pacientes, pero persistieron en otros. CONCLUSIONES: Teniendo en cuenta los datos en animales y la limitada experiencia humana, así como la falta de tratamientos alternativos disponibles para pacientes con envenenamiento, se requieren estudios adicionales con el uso cuidadoso de dosis altas de insulina en pacientes con envenenamiento grave por bloqueadores de canales de calcio.

Carlos da Camara RÉSUMÉ

Évaluer l’évidence relative à l’utilisation d’une thérapie insulinique à dose élevée associée à un supplément de dextrose et de potassium lors d’intoxication aux bloqueurs des canaux calciques. REVUE DE LITTÉRATURE: Une recherche informatisée sur MEDLINE et Toxline couvrant la période de 1966 à juillet 2004 utilisant les mots clés OBJECTIF:


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suivants: bloqueur des canaux calciques, surdosage, intoxication, antidote, et insuline a été effectuée. Les abrégés du “North American Congress of Clinical Toxicology” couvrant les années 1996 à 2003 furent également revisés. SÉLECTION DES ÉTUDES ET DE L’INFORMATION: Les articles identifiés incluant des études animales, des rapports de cas, et des séries de cas furent évalués. Aucune étude clinique n’est disponible. RÉSUMÉ: Les modèles animaux d’intoxication aux bloqueurs des canaux calciques ont démontré que des doses élevées d’insuline associées à un supplément de dextrose et de potassium sont une thérapie plus efficace que celle incluant le calcium, le glucagon, ou les catécholamines. Il semble que cette thérapie améliore le métabolisme cardiaque des carbohydrates, et qu’elle ait des effets inotropes positifs. L’expérience clinique publiée se limite à 13 rapports de cas où cette thérapie fut

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utilisée lors d’échec aux autres thérapies. Douze des 13 patients ont survécu. La thérapie insulinique à dose élevée fut bénéfique lors d’hypotension induite par les bloqueurs des canaux calciques, lors d’hyperglycémie, et lors d’acidose métabolique. La bradycardie et les blocs de conduction cardiaque se sont améliorés chez certains patients seulement. CONCLUSIONS: Basé sur les études animales, sur les quelques cas publiés, ainsi que sur l’inefficacité des autres thérapies lors d’intoxication significative, la thérapie insulinique à dose élevée nécessite des études supplémentaires et une utilisation judicieuse auprès de patients avec une intoxication sévère aux bloqueurs des canaux calciques.

2005 May, Volume 39

Marc M Perreault

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