Joel S. Holger

High-dose insulin therapy in beta-blocker and calcium channel-blocker poisoning

Introduction. High-dose insulin therapy, along with glucose supplementation, has emerged as an effective treatment for severe beta-blocker and calcium channel-blocker poisoning. We review the experimental data and clinical experience that suggests high-dose insulin is superior to conventional therapies for these poisonings. Presentation and general management. Hypotension, bradycardia, decreased systemic vascular resistance (SVR), and cardiogenic shock are characteristic features of beta-blocker and calcium-channel blocker poisoning. Initial treatment is primarily supportive and includes saline fluid resuscitation which is essential to correct vasodilation and low cardiac filling pressures. Conventional therapies such as atropine, glucagon and calcium often fail to improve hemodynamic status in severely poisoned patients. Catecholamines can increase blood pressure and heart rate, but they also increase SVR which may result in decreases in cardiac output and perfusion of vascular beds. The increased myocardial oxygen demand that results from catecholamines and vasopressors may be deleterious in the setting of hypotension and decreased coronary perfusion. Methods. The Medline, Embase, Toxnet, and Google Scholar databases were searched for the years 1975–2010 using the terms: high-dose insulin, hyperinsulinemia–euglycemia, beta-blocker, calcium-channel blocker, toxicology, poisoning, antidote, toxin-induced cardiovascular shock, and overdose. In addition, a manual search of the Abstracts of the North American Congress of Clinical Toxicology and the Congress of the European Association of Poisons Centres and Clinical Toxicologists published in Clinical Toxicology for the years 1996–2010 was undertaken. These searches identified 485 articles of which 72 were considered relevant. Mechanisms of high-dose insulin benefit. There are three main mechanisms of benefit: increased inotropy, increased intracellular glucose transport, and vascular dilatation. Efficacy of high-dose insulin. Animal models have shown high-dose insulin to be superior to calcium salts, glucagon, epinephrine, and vasopressin in terms of survival. Currently, there are no published controlled clinical trials in humans, but a review of case reports and case series supports the use of high-dose insulin as an initial therapy. High-dose insulin treatment protocols. When first introduced, insulin doses were cautiously initiated at 0.5 U/kg bolus followed by a 0.5–1 U/kg/h continuous infusion due to concern for hypoglycemia and electrolyte imbalances. With increasing clinical experience and the publication of animal studies, high-dose insulin dosing recommendations have been increased to 1 U/kg insulin bolus followed by a 1–10 U/kg/h continuous infusion. Although the optimal regimen is still to be determined, bolus doses up to 10 U/kg and continuous infusions as high as 22 U/kg/h have been administered with good outcomes and minimal adverse events. Adverse effects of high-dose insulin. The major anticipated adverse events associated with high-dose insulin are hypoglycemia and hypokalemia. Glucose concentrations must be monitored regularly and supplementation of glucose will likely be required throughout therapy and for up to 24 h after discontinuation of high-dose insulin. The change in serum potassium concentrations reflects a shifting of potassium from the extracellular to intracellular space rather than a decrease in total body stores. Conclusions. While more clinical data are needed, animal studies and human case reports demonstrate that high-dose insulin (1–10 U/kg/hour) is a superior treatment in terms of safety and survival in both beta-blocker and calcium-channel blocker poisoning. High-dose insulin should be considered initial therapy in these poisonings.

Intentional overdose with cardiac arrest treated with intravenous fat emulsion and high-dose insulin.

Introduction. Nebivolol, a beta blocker with 3–10 times more β1 cardioselectivity than metoprolol, has caused hypotension and bradycardia in overdose. We report a nebivolol-induced cardiac arrest in the setting of a polydrug ingestion, successfully resuscitated with intravenous fat emulsion (IFE) and high-dose insulin (HDI). Case report. A 48-year-old man was brought to the emergency department after ingesting nebivolol and ethanol, along with possibly diazepam and cocaine. He had a heart rate of 71/min and a blood pressure of 98/61 mmHg. The initial ECG showed sinus rhythm with a QTc of 483 ms and a QRS of 112 ms. Over the subsequent 4 h, he became bradycardic and hypotensive and developed bradyasystolic cardiac arrest. Standard resuscitation including epinephrine had no effect. Spontaneous circulation returned 30 s after a 100 mL bolus of 20% IFE, and the patient then became briefly hypertensive and tachycardic with heart rate and blood pressure measured as high as 123/min and 251/162 mmHg, respectively. His care included IFE infusion along with HDI bolus and infusion with doses as high as 21.8 units/kg/h. With subsequent hypotension, vasopressors were withheld in favor of HDI and supportive care. He was discharged with baseline neurologic function. Discussion. We hypothesize that after the administration of IFE the epinephrine was able to exert its effect on receptors previously occupied with the nebivolol. This would be congruent with the lipid sink theory of IFE mechanism. Conclusion. We report an overdose involving nebivolol in a polydrug ingestion resulting in cardiac arrest, successfully treated with IFE and a very HDI infusion.

Insulin versus vasopressin and epinephrine to treat β-blocker toxicity

Objective. We compared insulin and glucose (IN/G) to vasopressin plus epinephrine (V/E) in a pig model of β-blocker toxicity. Primary outcome was survival over four hours. Methods. Ten pigs received a 0.5 mg/kg bolus of propranolol IV followed by a continuous infusion. At the point of toxicity 20 ml/kg normal saline was rapidly infused and the propranolol drip continued at 0.125 mg/kg/min over four hours of resuscitation. Each pig was randomized to either IN/G or V/E. The V/E group began with epinephrine at 10 mcg/kg/min titrated up by 10 mcg/kg/min every 10 min to 50 mcg/kg/min or until baseline was obtained. Simultaneously, these pigs received vasopressin at 0.0028 units/kg/min, titrated upwards every 10 min to 0.014 units/kg/min or until baseline was obtained. The IN/G group began with a 2 units/kg/hr drip and increased by 2 units every 10 minutes to 10 units/kg/hr, or until baseline hemodynamics were obtained. CO, SVR, systolic blood pressure, HR, MAP, glucose, and potassium were monitored. Glucose was given for values <60 mg/dl. Results. The study was terminated early due to marked survival differences after five pigs were entered in each group. All IN/G group pigs survived four hours. All V/E group pigs died within 90 min. CO in the IN/G group increased throughout the four hours, rising above pre-propranolol levels, while MAP, SBP, and SVR all trended slightly downward. CO in the V/E group dropped until death, while MAP, SBP, and SVR rose precipitously until 30–60 minutes when these dropped abruptly until death. Glucose was required in the IN/G group. Conclusion. In this swine model, IN/G is superior to V/E to treat β-blocker toxicity. IN/G has marked inotropic properties while the vasopressor effects of V/E depress CO and contribute to death. Increasing SVR in this condition is detrimental to survival.

High-dose insulin: A consecutive case series in toxin-induced cardiogenic shock

Context. Cardiovascular medication overdoses can be difficult to treat. Various treatment modalities are currently recommended. Objective. To describe patient outcomes and adverse events of high-dose insulin therapy in consecutive overdose patients in cardiogenic shock after implementation of a high-dose insulin protocol (1–10 U/kg/h, while avoiding or tapering off vasopressors). Methods. This is an observational consecutive case series of patients identified from a registry. Data were collected by retrospective chart review of patients treated by our toxicology service with this protocol from February 2007 until March 2010. Results. Twelve patients were treated with high-dose insulin. The mean age was 36.5 years (SD 11.7). Seven patients had pre-existing vasopressor therapy, and all were tapered off vasopressors while on insulin. Two patients experienced pulseless electrical activity cardiac arrest prior to high-dose insulin therapy. Intravenous fat emulsion was given to two patients. The mean maximum insulin infusion rate was 8.35 U/kg/h (mean = 8.35, SD 6.34). The mean duration of insulin infusion was 23.5 h (SD 19.7). The mean duration of glucose infusion post-insulin was 25.2 h (SD 17.7). The primary toxins were β-blocker in five, calcium channel blocker in two, combined β-blocker/calcium channel blocker in two, tricyclic antidepressant in one, and polydrug in 2. Clinical outcomes. Eleven of 12 patients survived. One patient expired 9 h into insulin therapy from cardiac arrest shortly after the insulin was stopped and a vasopressor re-initiated (protocol deviation). Adverse events. Six patients experienced a total of 19 hypoglycemic events. Hypokalemia (defined as < 3.0 mEq/L) developed in eight patients. Adverse sequelae. Necrotic digits occurred in one patient with known clotting disorder after receiving high-dose norepinephrine and INR reversal with fresh frozen plasma prior to insulin therapy. One patient was discharged with mild anoxic injury thought due to pulseless electrical activity arrest prior to insulin therapy. Three of these 12 patients have been previously described in published case reports. Conclusion. High-dose insulin therapy based on a 1–10 U/kg/h dosing guideline and recommending avoidance of vasopressors appears to be effective in the treatment of toxin-induced cardiogenic shock. Hypoglycemia was the most frequent adverse event, followed by hypokalemia. Adverse events did not lead to adverse sequelae.

Methanol ingestion: prevention of toxic sequelae after massive ingestion.

Methanol ingestion, a rare but potentially fatal poisoning, is often difficult to diagnose in the emergency department (ED) and historically has been difficult to treat. In this article, we report a methanol ingestion with a blood concentration of 692 mg/dL, which was treated with 4-methylpyrazole (Fomepizole) and dialysis, without sequelae. To our knowledge, such a massive ingestion has never been treated with this modality without development of long-term disability. Another unusual feature of this case is the significantly elevated serum osmolal gap at presentation without elevation in anion gap, demonstrating the effects of co-ingestion of ethanol. Additionally, there was a marked disparity between the patients breath alcohol analyzer level and the blood ethanol concentration, illustrating the inability of the breath alcohol analyzer to differentiate between volatile alcohols. Treatment of the methanol-poisoned patient with Fomepizole is discussed.

Cardiotoxic Overdose Treated with Intravenous Fat Emulsion and High-Dose Insulin in the Setting of Hypertrophic Cardiomyopathy

High-dose insulin (HDI) and intravenous fat emulsion (IFE) are used in overdoses, although rarely combined. To our knowledge, IFE therapy has not been reported in overdoses of diltiazem, metoprolol and amiodarone. We report a severe overdose of these drugs treated with HDI and IFE in a patient with hypertrophic cardiomyopathy (HCM). We also discuss the potential clinical implications of the inotropic effects of HDI in the setting of HCM and the use and efficacy of IFE in this overdose.

Cardiovascular and metabolic effects of high-dose insulin in a porcine septic shock model.

OBJECTIVES High-dose insulin (HDI) has inotropic and vasodilatory properties in various clinical conditions associated with myocardial depression. The authors hypothesized that HDI will improve the myocardial depression produced by severe septic shock and have beneficial effects on metabolic parameters. In an animal model of severe septic shock, this study compared the effects of HDI treatment to normal saline (NS) resuscitation alone. METHODS Ten pigs were randomized to an insulin (HDI) or NS group. All were anesthetized and instrumented to monitor cardiovascular function. In both arms, Escherichia coli endotoxin lipopolysaccharide (LPS) and NS infusions were begun. LPS was titrated to 20 mug/kg/hour over 30 minutes and continued for 5 hours, and saline was infused at 20 mL/kg/hour throughout the protocol. Dextrose (50%) was infused to maintain glucose in the 60-150 mg/dL range, and potassium was infused to maintain a level greater than 2.8 mmol/L. At 60 minutes, the HDI group received an insulin infusion titrated from 2 to 10 units/kg/hour over 40 minutes and continued at that rate throughout the protocol. Survival, heart rate (HR), mean arterial pressure (MAP), pulmonary artery and central venous pressure, cardiac output, central venous oxygen saturation (SVO(2)), and lactate were monitored for 5 hours (three pigs each arm) or 7 hours (two pigs each arm) or until death. Cardiac index, systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), O(2) delivery, and O(2) consumption were derived from measured data. Outcomes from the repeated-measures analysis were modeled using a mixed-effects linear model that assumed normally distributed errors and a random effect at the subject level. RESULTS No significant baseline differences existed between arms at time 0 or 60 minutes. Survival was 100% in the HDI arm and 60% in the NS arm. Cardiovascular variables were significantly better in the HDI arm: cardiac index (p < 0.001), SVR (p < 0.003), and PVR (p < 0.01). The metabolic parameters were also significantly better in the HDI arm: SVO(2) (p < 0.01), O(2) delivery (p < 0.001), and O(2) consumption (p < 0.001). No differences in MAP, HR, or lactate were found. CONCLUSIONS In this animal model of endotoxemic-induced septic shock that results in severe myocardial depression, HDI is associated with improved cardiac function compared to NS resuscitation alone. HDI also demonstrated favorable metabolic, pulmonary, and peripheral vascular effects. Further studies may define a potential role for the use of HDI in the resuscitation of septic shock.

High dose insulin in toxic cardiogenic shock

Objective. To report the successful use of high dose insulin (HDI) in previously unreported insulin dosing ranges in a patient with severe myocardial toxicity due to an amitriptyline and citalopram overdose. Case Report. A 65-year-old female presented in respiratory arrest, which was followed by bradycardic pulseless electrical activity after ingesting multiple medications. After a prolonged resuscitation, the patient was maintained only on infusions of norepinephrine (40 mcg/min), vasopressin (4 units/h), insulin (80 units/h), and sodium bicarbonate. Due to a deteriorating clinical condition and limited prognosis, the insulin infusion was titrated incrementally upwards to 600 units/h (6 units/kg/h) over a 5 h time period while simultaneously completely weaning off both vasopressors. She developed brisk pulses and warm extremities, and her cardiac output nearly tripled. After 2 days of stabilization the insulin was slowly tapered, and the patient recovered. Discussion. HDI as a single cardiovascular agent significantly improved clinical and cardiovascular parameters after the failure of vasopressor therapy in severe cardiovascular toxicity. Higher doses of insulin than previously recommended may be needed in toxic poisonings when severe myocardial depression is present.

A Comparison of Vasopressin and Glucagon in Beta-Blocker Induced Toxicity

Objective. We compared the efficacy of vasopressin and glucagon in a porcine model of β-blocker toxicity. Our primary outcome was survival over 4 hours. Methods. Sixteen pigs received a 1-mg/kg bolus of propranolol IV followed by continuous infusion at 0.25 mg/kg/minute. Toxicity was defined as a 25% decrease in the product of heart rate (HR) and mean arterial pressure (MAP), at which point 20 mL/kg normal saline was rapidly infused. Each pig was randomly assigned to receive either vasopressin or glucagon after the saline bolus. The vasopressin group received a continuous infusion at 0.0028 U/kg/minute, titrated up to a maximum of 0.014 U/kg/minute. The glucagon group received a 0.05-mg/kg bolus followed by continuous infusion at 0.15 mg/kg/hour. The HR, MAP, systolic BP (SBP), cardiac output (CO), glucose, and pH were monitored for 4 hours from toxicity or until death. Results. One pig survived at 4 hours (vasopressin group). Analysis of the 4-hour Kaplan-Meier survival curves found no differences between the groups (log-rank test 0.059, p = 0.81). No overall differences were identified in MAP, systolic BP, cardiac output, glucose, pH, or HR. However, over the first hour MAP and SBP were significantly higher in the vasopressin group (p = 0.004, p = 0.006, respectively). Conclusion. In this β-blocker toxicity model, there were no differences in the survival curves between vasopressin- and glucagon-treated pigs during a 4-hour analysis period. No overall differences were noted in MAP, systolic BP, CO, HR, pH, or glucose levels, although vasopressin treatment yielded higher MAP and systolic BP early in resuscitation.

A blinded, randomized, controlled trial of three doses of high-dose insulin in poison-induced cardiogenic shock

Background. High dose insulin (HDI) has proven superior to glucagon and catecholamines in the treatment of poison-induced cardiogenic shock (PICS) in previous animal studies. Standard recommendations for dosing of insulin vary and the optimal dose of HDI in PICS has not been established. Our hypothesis was a dose of 10 U/kg/hr of HDI would be superior to 1 U/kg/hr with cardiac output (CO) as our primary outcome measure in pigs with propranolol-induced PICS. Methods. This was a blinded, prospective, randomized trial with 4 arms consisting of 4 pigs in each arm. The arms were as follows: placebo (P), 1 U/kg/hr (HDI-1), 5 U/kg/hr (HDI-5), and 10 U/kg/hr (HDI-10). Cardiogenic shock was induced with a bolus of 0.5 mg/kg of propranolol followed by an infusion of 0.25 mg/kg/min until the point of toxicity, defined as 0.75 x (HR x MAP) was reached. At this point the propranolol infusion was decreased to 0.125 mg/kg/min and a 20 mL/kg bolus of normal saline (NS) was administered. The protocol was continued for 6 hours or until the animals died. Results. 2 pigs died in the P arm, 1 pig died each in the HDI-1 and HDI-5 arms, and all pigs lived in the HDI-10 arm. There was a statistically significant difference in dose by time interaction on CO of 1.13 L/min over the 6 hr study period (p = < 0.001). There was also a statistically significant difference in dose by time interaction on MAP, HR, and systemic vascular resistance (SVR). No statistically significant difference was found between any of the arms regarding glucose utilization. Conclusion. HDI was statistically and clinically significantly superior to placebo in this propranolol model of PICS. Furthermore a dose response over time was found where CO increased corresponding to increases in doses of HDI.