Historical Introduction of High-Dose Insulin Euglycemia Therapy
High-dose insulin euglycemia (HDIE) therapy was first introduced in the late 1990s as a treatment for calcium channel blocker overdose, with initial cautious dosing protocols starting at 0.5 U/kg bolus followed by 0.5-1 U/kg/hr infusions due to concerns about hypoglycemia and electrolyte imbalances. 1
Evolution of the Therapy
The development and adoption of HDIE therapy followed a progressive timeline:
Initial experimental phase (1975-1997): Early animal models and experimental studies began exploring the use of high-dose insulin in cardiovascular toxicity, laying the groundwork for clinical application. 1
Clinical introduction (late 1990s): The therapy transitioned from experimental models to human use, initially with conservative dosing strategies of 0.5 U/kg bolus and 0.5-1 U/kg/hr continuous infusion. 1
Expanded clinical experience (2006-2010): By 2006, HDIE was being recognized as a superior adjunctive approach compared to conventional pharmacological treatments including calcium salts, epinephrine, and glucagon, though clinical experience remained limited to isolated cases and short series. 2
Guideline incorporation (2010): The American Heart Association formally included high-dose insulin therapy in their 2010 guidelines for cardiac arrest in special situations, recommending 1 U/kg regular insulin bolus with 0.5 g/kg dextrose, followed by continuous infusions of 0.5-1 U/kg/hr insulin. 3
Current standard practice (2017-present): Modern guidelines from the Society of Critical Care Medicine recommend HDIE as a first-line treatment with more aggressive dosing: 1 U/kg bolus followed by 1 U/kg/hr infusion, with maintenance of euglycemia and close potassium monitoring. 3
Dosing Evolution Over Time
The progression from cautious to aggressive dosing reflects growing clinical confidence:
Early protocols used 0.5 U/kg bolus and 0.5-1 U/kg/hr infusions due to safety concerns. 1
With increasing clinical experience and animal study publications, recommendations increased to 1 U/kg bolus followed by 1-10 U/kg/hr continuous infusion. 1
Bolus doses up to 10 U/kg and continuous infusions as high as 22 U/kg/hr have been successfully administered with good outcomes and minimal adverse events. 1
Current standard protocols call for 1 U/kg bolus followed by 1 U/kg/hr infusion, with titration based on hemodynamic response. 3
Key Mechanistic Understanding
The therapy's adoption was driven by understanding three main mechanisms of benefit:
Increased inotropy: Direct positive inotropic effects on myocardial contractility. 1, 3
Enhanced glucose metabolism: Allows cellular switch from fatty acid to carbohydrate metabolism, particularly important in stressed myocardium and vascular smooth muscle. 2
Vascular effects: Restoration of peripheral vascular resistance. 2
Clinical Evidence Supporting Adoption
Animal studies demonstrated HDIE superiority over calcium salts, glucagon, epinephrine, and vasopressin in terms of survival, which drove clinical adoption despite the initial lack of controlled human trials. 1
Human case series from 1997-2018 showed success rates ranging from 80.4-100%, further solidifying its role as standard therapy. 4