ABSTRACT

Life-threatening cardiovascular collapse symptoms can develop due to calcium channel and beta-receptor blocker overdose and there are no specific antidotes for treatment.

A 13-year-old girl was admitted with severe hypotension and bradycardia after ingestion of an overdose carvedilol and verapamil. Cardiovascular collapse was resistant to fluid therapy, calcium gluconat and high-dose vasopressor infusion. Intravenous lipid infusion was administered in the patient who had resistant hypotension with hiperinsulinemic euglycemia on the first hour of hospitalization. Hemodynamic stability of the patient was achieved 30 minutes after lipid administration.

Calcium channel and beta-receptor blocker overdose may result in life-threatening intoxication. Classical therapies suggested for these intoxications can be insufficient. Favorable results can be obtained after intravenous lipid infusion. With this report, we aimed to draw attention to those intoxications that can be life-threatening and emphasize that intravenous lipid infusion therapy can be successful in patients refractory to other treatments.

Introduction

Calcium channel blocker (CCB) and β receptor blocker (BB) overdoses constitute a small percentage among all intoxications.¹ According to the 2014 Annual Report of the American Association of Poison Control Center’s National Poison Data System, 0.6% of all overdoses occur with CCB and 0.9% take place with BB.² However, these overdoses lead to severe toxicity and their mortality rates are quite high.³ BB drugs cause hypotension and bradycardia by attaching to the beta adrenoceptors.⁴ In some BB overdoses, however, since the drug has lipid resolution, central nervous system findings (such as seizure, respiratory depression, coma) can be observed.⁴ Following the excessive intake of CCB and BB drugs, treatments, such as glucagon, calcium gluconate, and hyperinsulinemic euglycemia therapy (HIET) as well as vasopressor drugs and intravenous fluid therapy are used in cases with cardiovascular collapse.⁵ Lately, in CCB and BB poisonings unresponsive to standard therapy, Recently, intravenous lipid infusion (ILI) therapy, which is used for poisoning with lipophilic local anesthetics and chemical agents, is a new therapy option when the standard therapy is inefective for poisoning with CCB and BB intoxications.⁵ A variety of theories have been suggested on the mechanism of action of ILI. According to the “lipid-sink theory”; ILI holds the lipophilic drugs where by forming a separate compartment in plasma and reduces the unwanted side effects of these drugs. Meanwhile, it also decreases toxic effects by drawing drugs that entered into cells to the extracellular field; namely, plasma. Free fatty acids contribute to inotropic effect by providing energy substrate to depressed myocardium.⁶ In addition, in myocardium with poor contractility, ILI administration has been claimed to cause positive inotropic and chronotropic effects by ameliorating functions of ion channels (like sodium and calcium) located on cell membranes.⁷

In this paper, we aimed to emphasize the effectiveness of ILI therapy in a pediatric patient who developed severe cardiovascular toxicity following high-dose BB and CCB drugs resistant to standard therapies.

Discussion

CCB and BB intoxications can cause life-threatening conditions and they are treated with similar treatment principles. In the treatment of hypotension and cardiovascular collapse developed in overdoses of these drugs; fluid, vasopressor, inotrope and chronotrope agents are used. In the treatment of cardiovascular collapse, glucagon, calcium, and ILI treatment can be applied in cases refractory to intravenous fluid and catecholamines.⁵ In our case, cardiopulmonary resuscitation was necessary following CCB and BB overdose; resistant hypotension did not ameliorate despite fluid, catecholamine, calcium, glucagon, and high-dose insulin treatment; the patient was discharged from the hospital without any sequelae after ILI treatment.

HIET has numerous positive effects in cardiogenic shock developed in CCB and BB intoxication. In animal models of propranolol and verapamil toxicity; it has been shown that survival rate increased and they ensured good hemodynamic stability when HIET was added compared to adrenalin and glucagon application alone.⁵ Following HIET, the effect of the treatment begins between 15 and 60 minutes.⁵ It is recommended that HIET should be commenced in cardiogenic shock and 0.5-2 U/ kg/hour maintenance infusion treatment is suggested following 0.5-1 U/kg load dose.⁵ In our case, after a loading dose of 1 U/kg intravenous insulin, the infusion of 0.5 U/kg/hour was started and finally was increased up to 2 U/kg/hour. Some amount of dose could be reduced in vasopressors with insulin bolus administration for a short time. However, permanent hemodynamic stability could not be enabled with insulin administration.

ILI treatment is recommended as a rescue therapy in cases of severe overdose of lipophilic anesthetics largely and other drugs.⁹ Most studies carried out regarding ILI treatment were performed in CCB overdoses due to high lipophility. Five minutes after applying verapamil to 30 rats at toxic dose, Tebbutt et al.¹⁰ administered serum physiologic infusion to rats in control group over a five-minute period, and 12 mL/kg of 20% lipid infusion to those in study group. They showed that survival rate increased in the lipid-administered group. In addition, lipid therapy doubled the average lethal dose of verapamil. The first lipid treatment was successfully applied in a case with intravenous bupivacaine toxicity in 2006.¹¹ One hundred and three cases with single or multiple drug overdoses including local anesthetics with lipid and water solubility, antidepressant, antipsychotic, and cardiovascular drugs were retrospectively evaluated and it was reported that the positive effects of the treatment were not observed in only 16 cases (15.5%). In 10 cases out of 12 with verapamil overdose and two cases with carvedilol overdose, the positive effects of lipid therapy were reported.¹² Graudins et al.⁵ have reported that the positive effects of ILI applied as a rescue therapy in CCB and BB multiple drug overdoses were seen in some cases in an hour and a few hours in some patients. While the efficiency of ILI application was shown in BB and CCB overdoses, the recommended dose range is still controversial. The ILI  dose according to the proposal of the American Regional Anesthesia Association in 2012 was intravenous bolus of 20% lipid emulsion, 1.5 mL/kg of lean body mass, (can be repeated in persistent cardiovascular collapse) or it was in a continuous infusion way as 0.25-0.5 mL/kg/min.⁸ In a retrospective study of nine adult patients, bolus application was compared with continuous infusion application. No significant difference was determined on the average arterial pressures.¹³ Despite 2 U/kg/hour insulin infusion in our case poisoned with carvedilol and verapamil in lipophilic characteristic^14,15, bolus ILE application was given at a dose of 1.5 mL/kg in the 1^st hour of follow-up (20% intralipid^®) and hemodynamic stability was ensured in half an hour. Vasopressor drugs could be decreased rapidly, ILI therapy was not required again. Potential side effects of ILI therapy were reported to be lipemic plasma, biochemistry laboratory abnormalities, hyperviscosity, pancreatitis, and noncardiogenic pulmonary edema.⁵ No side effect was observed in our case following ILI therapy.

Poisonings of CCB and BB can be life-threatening. Recommended standard therapies can be inadequate in these poisonings. ILI treatment can be a life-saving treatment option in patients with CCB and BB intoxication who do not respond to classical supportive therapy and can develop life-threatening cardiovascular collapse.