Reviewed and revised 17 December 2015
- High-dose Insulin Euglycaemic Therapy (HIET) is primarily used in the therapy of severe calcium channel blocker toxicity
- HIET can also be used for severe beta blocker toxicity and potentially other toxicities/ presentations requiring inotropic support
MECHANISM OF ACTION
HIET may allow the heart to overcome the ‘metabolic starvation’ that results from calcium channel blocker toxicity (and other poisonings, such as beta blockers), which compounds the direct cardiotoxic effects.
Calcium channel blocker overdoses can result in:
- hypoinsulinaemia, as insulin release is dependent on calcium influx into islet beta cells through L-type calcium channels
- calcium channel blocker-induced insulin resistance
- calcium channel blockers also impair the cardiac myocyte adaptive response of shifting from using free fatty acids, their favoured “resting state” energy substrate, to carbohydrates, due to:
- impaired uptake of glucose and free fatty acids by cardiac myocytes
- inhibition of calcium-dependent mitochondrial activity required for glucose catabolism
The effects of insulin are numerous:
- increased glucose and lactate uptake by myocardial cells
- improved myocardial function without increased oxygen demand
- increased pyruvate dehydrogenase activity, thus hastening myocardial lactate oxidation and clear the cytosol of glycolytic byproducts that can impair calcium handling and cause diastolic dysfunction.
- promotes excitation–contraction coupling and contractility because increased glucose availability results in:
- increased sarcoplasmic reticulum-associated calcium ATPase activity
- increased cytoplasmic calcium concentrations
- enhanced calcium entrance into mitochondria and sarcolemma
HIET may be best used adjunctively with other measures such as catecholamines, for two reasons:
- insulin-mediated inotropy is not catecholamine-mediated, and is not affected by β blockers, so additive effects are likely
- although insulin appears to improve myocardial contractility, it has no chronotropic effect and may cause vasodilation
DOSING AND PROTOCOL
Recommended high-dose insulin euglycaemic therapy protocol based on the clinical experience of the Western Australian Toxicology Service, published case reports, reviews and animal studies (from Nickson and Little, 2009):
Adverse events are predictable, uncommon and easily managed.
For instance, there were NO adverse effects in these extreme examples:
- the inadvertent administration of a 1000 IU insulin loading dose for verapamil toxicity
- treatment of toxic cardiogenic shock for 2 days with a 6 IU/kg/h insulin infusion
Adverse effects of HIET include:
- hypoglycaemia (<3.3 mmol/L in about 16% of cases)
- Some cases of severe calcium channel blocker toxicity in patients presenting with hyperglycaemia do not require any additional glucose administration despite high-dose insulin therapy.
- hypoglycaemia may be more likely in milder cases without marked hypotension.
Hypokalaemia (potassium < 3.5 mmol/L)
- noted in only two of seven in Greene et al’s small series, with a minimum potassium level of 2.8 mmol/L.
- Excessive correction of hypokalaemia should be avoided, because it reflects the intracellular shift of potassium from the extracellular compartment due to the action of insulin, rather than a potassium-depleted state.
- Hypokalaemia in HIET may actually be beneficial:
- it may augment myocardial contractility by enhancing calcium entry during systole
- increased intracellular potassium may have a membrane-stabilising effect in excitable cells
- HIET (high-dose insulin euglycaemic therapy) was first used to treat verapamil toxicity in humans in 1993, with a favourable outcome.
- Since then, in addition to animal studies, there have been >70 cases reporting the beneficial use of HIET in humans, with an overall survival rate of 85%.
- HIET has gained widespread acceptance as a core therapy for calcium channel blocker toxicity among clinical toxicologists, even though no randomised controlled trials have been performed to test its efficacy.
References and Links
- Greene SL, Gawarammana I, Wood DM, Jones AL, & Dargan PI (2007). Relative safety of hyperinsulinaemia/euglycaemia therapy in the management of calcium channel blocker overdose: a prospective observational study. Intensive care medicine, 33 (11), 2019-24 PMID: 17622512
- Nickson CP, & Little M (2009). Early use of high-dose insulin euglycaemic therapy for verapamil toxicity. The Medical journal of Australia, 191 (6), 350-2 PMID: 19769561 (abstract and pdf link)
FOAM and web resources
- TPR — There is no real evidence on treating calcium channel blocker overdose (2014)
- TPR — Are vasopressors effective therapy in calcium channel blocker overdose? (2013)
- TPR — Pressors or high-dose insulin for calcium channel blocker overdose? (2013)
Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also a Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.
After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.
He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE. He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.
His one great achievement is being the father of three amazing children.
On Twitter, he is @precordialthump.