High-dose insulin euglycaemic therapy (HIET), dosing

Clinical background

High-dose insulin euglycaemic therapy (HIET) is a specific antidotal treatment for cardiogenic shock caused by calcium channel blocker or beta blocker poisoning. The need for a structured dosing tool arises because the doses are one to two orders of magnitude above those used in diabetes, because titration is against haemodynamics and not against the blood glucose, and because the treatment requires concurrent glucose administration and potassium monitoring if it is not to cause harm. Conventional measures such as atropine, glucagon and calcium salts often fail in severe poisoning, and catecholamines may worsen perfusion by increasing afterload and myocardial oxygen demand in an already depressed heart [1]. The three main mechanisms of HIET are increased inotropy, increased intracellular glucose transport into the failing myocardium, and peripheral vasodilation that lowers afterload [1].

Calculating high-dose insulin euglycaemic therapy

The calculator computes two components: an intravenous bolus dose and a continuous infusion, both using regular (soluble) insulin.

$$\text{Bolus} = 1 \text{ U/kg regular insulin IV}$$

$$\text{Infusion} = \text{Body weight (kg)} \times \text{Infusion rate (U/kg/h)}$$

The infusion rate is chosen from fixed steps: 0.5, 1, 2, 5 or 10 U/kg/h, with 10 U/kg/h as the maximum dose. Start at 0.5 to 1 U/kg/h and titrate upwards according to the haemodynamic response. The bolus dose is constant regardless of the infusion rate chosen.

The dosing regimen was derived from a synthesis of experimental data and clinical experience published in 2011, which searched the literature from 1975 to 2010 and identified 72 relevant articles among 485 hits [1]. The underlying material consisted of animal models and human case reports and case series, not controlled clinical trials. A cautious starting dose of a 0.5 U/kg bolus followed by 0.5 to 1 U/kg/h was originally recommended, but with growing clinical experience and support from animal studies the recommendation was raised to a 1 U/kg bolus followed by an infusion of 1 to 10 U/kg/h [1]. In case reports, bolus doses of up to 10 U/kg and infusions of up to 22 U/kg/h have been given with good outcomes and few adverse effects [1].

Interpretation in practice

HIET is not an instrument with risk bands in the traditional sense, but a titration algorithm in which the dose step is governed by the patient's haemodynamic response. The calculator's fixed steps correspond to the clinical practice described in expert consensus and case series.

The inotropic effect is delayed by 15 to 60 minutes after starting [1]. This means that the decision to escalate should not be made too early, but also that HIET should be started early rather than as a last resort when other measures have failed. Concurrent glucose infusion is mandatory from the outset, and the plasma glucose should be checked every 15 to 30 minutes initially. Potassium shifts into the cells and must be replaced.

Validation and performance

There are no controlled clinical trials of HIET in humans [1, 3]. The evidence rests on animal models, case reports, case series and a few observational studies. A systematic review from 2014 identified only three human observational studies of HIET in calcium channel blocker poisoning, of which two compared different HIET regimens and one compared HIET with vasopressors [3]. All showed improved haemodynamics, and animal studies showed a survival advantage over calcium, glucagon, epinephrine and vasopressin [1, 3]. The quality of the evidence was judged to be low throughout [3].

The largest published clinical experience is a structured chart review from a US poison control centre comprising 199 patients who received HIET (defined as an infusion of at least 0.5 U/kg/h) for beta blocker or calcium channel blocker poisoning between 2007 and 2016 [4]. The median age was 48 years; 44 per cent had been poisoned with a beta blocker, 33 per cent with a calcium channel blocker and 23 per cent with both. The median nadir systolic blood pressure was 70 mmHg. The median bolus dose was 1 U/kg and the median starting infusion 1 U/kg/h, with a median maximum infusion of 8 U/kg/h. Cardiac arrest occurred in 21 per cent and mortality was 16 per cent [4]. The study has no control group, so the mortality figure cannot be interpreted as a treatment effect.

A literature review from 2018 examining published case series reported a success rate of 80.4 to 100 per cent, defined as haemodynamic improvement or survival [5]. The definitions of success varied between studies, however, and the material is dominated by case reports with inherent publication bias.

Limitations

HIET applies to cardiogenic shock in calcium channel blocker or beta blocker poisoning. There is no evidence that the principle works in other forms of toxin-induced cardiomyopathy, and the calculator should not be used for other poisonings.

The most important adverse effects are hypoglycaemia and hypokalaemia. In the largest case series, hypokalaemia occurred in 29 per cent and hypoglycaemia in 31 per cent of patients [4]. Hypoglycaemia was commoner when the glucose infusion was less concentrated: 50 per cent of patients receiving a glucose concentration of 10 per cent or lower developed hypoglycaemia, compared with 30 per cent at 20 per cent or higher [4]. Glucose monitoring must continue for up to 24 hours after HIET is stopped, since insulin levels persist [1]. The fall in potassium reflects an intracellular shift rather than a total body loss, but still requires replacement to avoid arrhythmias.

A further limitation is that the dose range of 0.5 to 10 U/kg/h rests on expert consensus and case series, not on dose-finding studies [2]. The 2017 expert consensus explicitly recommends that doses up to 10 U/kg/h be used only in patients who do not respond to first-line treatment, and notes that the level of evidence for all interventions in calcium channel blocker poisoning is very low [2].

The calculator does not handle paediatric dosing separately, but the dosing principle is the same in children. Its application does, however, require consultation with a poisons information service.

References

1. Engebretsen KM et al. High-dose insulin therapy in beta-blocker and calcium channel-blocker poisoning. Clin Toxicol (Phila). 2011;49(4):277-83. PMID: 21563902
2. St-Onge M et al. Experts Consensus Recommendations for the Management of Calcium Channel Blocker Poisoning in Adults. Crit Care Med. 2017;45(3):e306-e315. PMID: 27749343
3. St-Onge M et al. Treatment for calcium channel blocker poisoning: a systematic review. Clin Toxicol (Phila). 2014;52(9):926-44. PMID: 25283255
4. Cole JB et al. High dose insulin for beta-blocker and calcium channel-blocker poisoning. Am J Emerg Med. 2018;36(10):1817-1824. PMID: 29452919
5. Krenz JR, Kaakeh Y. An Overview of Hyperinsulinemic-Euglycemic Therapy in Calcium Channel Blocker and β-blocker Overdose. Pharmacotherapy. 2018;38(11):1130-1142. PMID: 30141827